Analyte sensor

ABSTRACT

Systems and methods of use for continuous analyte measurement of a host&#39;s vascular system are provided. In some embodiments, a continuous glucose measurement system includes a vascular access device, a sensor and sensor electronics, the system being configured for insertion into communication with a host&#39;s circulatory system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.12/055,114 filed Mar. 25, 2008; and is a continuation-in-part of U.S.application Ser. No. 12/055,203 filed Mar. 25, 2008. U.S. applicationSer. No. 12/055,203 is a continuation-in-part of U.S. application Ser.No. 11/691,466 filed Mar. 26, 2007; and is a continuation-in-part ofU.S. application Ser. No. 11/691,424 filed Mar. 26, 2007; and is acontinuation-in-part of U.S. application Ser. No. 11/691,432 filed Mar.26, 2007; and is a continuation-in-part of U.S. application Ser. No.11/691,426 filed Mar. 26, 2007. U.S. application Ser. No. 12/055,114 isa continuation-in-part of U.S. application Ser. No. 11/691,466 filedMar. 26, 2007; and is a continuation-in-part of U.S. application Ser.No. 11/691,424 filed Mar. 26, 2007; and is a continuation-in-part ofU.S. application Ser. No. 11/691,432 filed Mar. 26, 2007; and is acontinuation-in-part of U.S. application Ser. No. 11/691,426 filed Mar.26, 2007. U.S. application Ser. No. 11/691,466 filed Mar. 26, 2007 is acontinuation-in-part of U.S. application Ser. No. 11/543,396 filed Oct.4, 2006; and is a continuation-in-part of U.S. application Ser. No.11/543,490 filed Oct. 4, 2006; and is a continuation-in-part of U.S.application Ser. No. 11/543,404 filed Oct. 4, 2006. U.S. applicationSer. No. 11/691,432 filed Mar. 26, 2007 is a continuation-in-part ofU.S. application Ser. No. 11/543,396 filed Oct. 4, 2006; and is acontinuation-in-part of U.S. application Ser. No. 11/543,490 filed Oct.4, 2006; and is a continuation-in-part of U.S. application Ser. No.11/543,404 filed Oct. 4, 2006. U.S. application Ser. No. 11/691,426filed Mar. 26, 2007 is a continuation-in-part of U.S. application Ser.No. 11/543,396 filed Oct. 4, 2006; and is a continuation-in-part of U.S.application Ser. No. 11/543,490 filed Oct. 4, 2006; and is acontinuation-in-part of U.S. application Ser. No. 11/543,404 filed Oct.4, 2006. U.S. application Ser. No. 11/691,424 filed Mar. 26, 2007 is acontinuation-in-part of U.S. application Ser. No. 11/543,396 filed Oct.4, 2006; and is a continuation-in-part of U.S. application Ser. No.11/543,490 filed Oct. 4, 2006; and is a continuation-in-part of U.S.application Ser. No. 11/543,404 filed Oct. 4, 2006. The disclosures ofeach of the abovementioned applications is hereby expressly incorporatedby reference in its entirety and is hereby expressly made a portion ofthis application.

FIELD OF THE INVENTION

The preferred embodiments relate generally to systems and methods formeasuring an analyte in a host.

BACKGROUND OF THE INVENTION

In today's medical practice, analyte levels in patient biologicalsamples (e.g., fluids, tissues and the like collected from patients) areroutinely measured during the process of diagnosing, monitoring and/orprognosticating a patient's medical status. For example, a basicmetabolic panel (e.g., BMP or chem.-7) measures sodium, potassium,chloride, bicarbonate, blood urea nitrogen (BUN), creatinine andglucose. Bodily sample analyte tests are routinely conducted in avariety of medical settings (e.g., doctor's office, clinic, hospital, bymedical personnel) and in the home by the host and/or a caretaker. Forexample, some medical conditions require frequent testing of bloodanalyte levels. For example, diabetes mellitus, a disorder in which thepancreas cannot create sufficient insulin (Type I or insulin dependent)and/or in which insulin is not effective (Type 2 or non-insulindependent), is one exemplary medical condition, wherein bodily fluidsamples (e.g., blood, interstitial fluid) are routinely tested, in orderto ascertain the patient's (e.g., host's) glucose status, often by thehost or a caretaker. In the diabetic state, the victim suffers from highblood sugar, which can cause an array of physiological derangementsassociated with the deterioration of small blood vessels, for example,kidney failure, skin ulcers, or bleeding into the vitreous of the eye. Ahypoglycemic reaction (low blood sugar) can be induced by an inadvertentoverdose of insulin, or after a normal dose of insulin orglucose-lowering agent accompanied by extraordinary exercise orinsufficient food intake.

Conventionally, a person admitted to a hospital for certain conditions(with or without diabetes) is tested for blood sugar level by a singlepoint blood glucose meter, which typically requires uncomfortable fingerpricking methods or blood draws and can produce a burden on the hospitalstaff during a patient's hospital stay. Due to the lack of convenience,blood sugar glucose levels are generally measured as little as once perday or up to once per hour. Unfortunately, such time intervals are sofar spread apart that hyperglycemic or hypoglycemic conditionsunknowingly occur, incurring dangerous side effects. It is not onlyunlikely that a single point value will not catch some hyperglycemic orhypoglycemic conditions, it is also likely that the trend (direction) ofthe blood glucose value is unknown based on conventional methods. Thisinhibits the ability to make educated insulin therapy decisions.

A variety of sensors are known that use an electrochemical cell toprovide output signals by which the presence or absence of an analyte,such as glucose, in a sample can be determined. For example, in anelectrochemical cell, an analyte (or a species derived from it) that iselectro-active generates a detectable signal at an electrode, and thissignal can be used to detect or measure the presence and/or amountwithin a biological sample. In some conventional sensors, an enzyme isprovided that reacts with the analyte to be measured, and the byproductof the reaction is qualified or quantified at the electrode. An enzymehas the advantage that it can be very specific to an analyte and also,when the analyte itself is not sufficiently electro-active, can be usedto interact with the analyte to generate another species which iselectro-active and to which the sensor can produce a desired output. Inone conventional amperometric glucose oxidase-based glucose sensor,immobilized glucose oxidase catalyses the oxidation of glucose to formhydrogen peroxide, which is then quantified by amperometric measurement(for example, change in electrical current) through a polarizedelectrode.

SUMMARY OF THE INVENTION

In a first aspect, an integrated sensor system is provided for measuringan analyte in a sample of a host and for fluid infusion into the host,comprising: an analyte sensor configured and arranged for measuring ananalyte concentration in a biological sample of a circulatory system ofa host; a vascular access device; tubing assembly comprising tubing; anda flow control device configured to regulate exposure of the analytesensor to a biological sample and to a reference solution according to aflow profile, wherein the flow control device comprises a valve, andwherein the valve is configured and arranged with a gravity flowposition and a controlled flow position.

In an embodiment of the first aspect, the system is configured such thatthe analyte sensor is flushed by the reference solution when the valveis in the gravity flow position.

In an embodiment of the first aspect, the gravity flow positioncomprises a first flow rate of the solution, wherein the controlled flowposition comprises a second flow rate of the solution, and wherein aratio of the first flow rate to the second flow rate is at least about10:1.

In an embodiment of the first aspect, the gravity flow position has aflow rate of at least about 600 ml/hr.

In an embodiment of the first aspect, the controlled flow position has aflow rate of from about 0.5 ml/hr to about 4.0 ml/hour.

In an embodiment of the first aspect, the valve is configured andarranged to receive the tubing in a substantially linear configuration.

In an embodiment of the first aspect, the valve and the tubing assemblyare configured and arranged such that the tubing is in a stretched stateafter installation of the tubing in the valve.

In an embodiment of the first aspect, valve is configured and arrangedsuch that the tubing is substantially linear in the gravity flowposition and the tubing is substantially non-linear in the controlledflow position.

In an embodiment of the first aspect, the valve is configured andarranged to preclude tubing installation when the valve is in thecontrolled flow position.

In an embodiment of the first aspect, the valve is configured andarranged to receive the tubing assembly in only one orientation.

In an embodiment of the first aspect, the valve and tubing assembly areconfigured and arranged to releasably interlock such that a portion ofthe valve mechanically interlocks with a portion of the tubing assembly.

In an embodiment of the first aspect, the vascular access device and thetubing assembly are configured and arranged to substantially precluderotational movement between the vascular access device and the tubingassembly when engaged.

In an embodiment of the first aspect, the system further comprises afree-flow mitigation device.

In an embodiment of the first aspect, the free-flow mitigation devicecomprises a spring clip occluder located on the tubing assembly.

In an embodiment of the first aspect, the system is configured forelectronic control of the free-flow mitigation device.

In an embodiment of the first aspect, the system further comprises anelectronic solenoid associated with the flow control device, wherein theelectronic solenoid provides electronic control of the free-flowmitigation device.

In an embodiment of the first aspect, the system is configured andarranged such that the free-flow mitigation device precludes flowresponsive to at least one of power removal, loss to the system, andloss to the flow control device.

In an embodiment of the first aspect, the system is configured andarranged such that the free-flow mitigation device is controlled atleast in part by the flow profile.

In an embodiment of the first aspect, the system further comprises anintravenous bag containing a reference solution, wherein the referencesolution has a known analyte concentration.

In an embodiment of the first aspect, the analyte sensor is configuredto measure at least one analyte selected from the group consisting ofalbumin, alkaline phosphatase, alanine transaminase, aspartateaminotransferase, bilirubin, blood urea nitrogen, calcium, carbondioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase,hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH,phosphorus, potassium, sodium, total protein, uric acid, a metabolicmarker and a drug.

In a second aspect, a system configured to measure at least one analytein a host is provided, the system comprising: a vascular access devicecomprising a first portion configured for insertion into a host and asecond portion configured to remain outside the host after insertion ofthe first portion; at least one analyte sensor located within the secondportion of the vascular access device, such that the at least oneanalyte sensor is exposed to a biological sample when the biologicalsample is drawn back by a distance of about 40 mm or less into thevascular access device, when the vascular access device is in fluidcommunication with a circulatory system of the host; and a flow controldevice configured to regulate exposure of the at least one analytesensor to a biological sample and to a reference solution according to aflow profile.

In an embodiment of the second aspect, the at least one analyte sensoris exposed to the biological sample when a volume of about 300 μl orless of the biological sample is drawn back.

In an embodiment of the second aspect, the at least one analyte sensoris exposed to the biological sample when a volume of about 200 μl orless of the biological sample is drawn back.

In an embodiment of the second aspect, the vascular access devicecomprises a catheter.

In an embodiment of the second aspect, the second portion comprises aconnecting end of the catheter, wherein the connecting end is configuredfor connection to tubing.

In an embodiment of the second aspect, the vascular access device is acatheter, and wherein the catheter is 22 gauge or smaller.

In an embodiment of the second aspect, the second portion comprises afluid coupler, wherein the fluid coupler is configured to releasablymate with the catheter.

In an embodiment of the second aspect, the at least one sensor isincorporated into the second portion.

In an embodiment of the second aspect, the at least one sensor islocated on an inner surface of the second portion.

In an embodiment of the second aspect, the at least one sensor isdisposed within a lumen of the second portion.

In an embodiment of the second aspect, at least a portion of the atleast one sensor is disposed in an orientation substantially parallel toa longitudinal axis of the second portion.

In an embodiment of the second aspect, at least a portion of the atleast one sensor is disposed in an orientation substantiallyperpendicular to a longitudinal axis of the second portion.

In an embodiment of the second aspect, the at least one sensor comprisesan exposed electroactive surface area with a dimension substantiallyequal to a width of a lumen of the second portion.

In an embodiment of the second aspect, the exposed electroactive surfacearea intersects the lumen of the second portion.

In an embodiment of the second aspect, the second portion is configuredto provide identification information associated with the flow profile.

In an embodiment of the second aspect, the system is configured toprogram the flow profile of the flow control device in response to anautomatic receipt of the identification information.

In an embodiment of the second aspect, the identification information isprovided by a mechanical structure of the second portion.

In an embodiment of the second aspect, the identification information isprovided by electronics of the second portion.

In an embodiment of the second aspect, the vascular access devicecomprises at least two lumens, and wherein the system is configured andarranged to infuse a fluid into a first lumen of the vascular accessdevice, and wherein the system is configured and arranged to draw back abiological sample into a second lumen of the vascular access device.

In an embodiment of the second aspect, the at least one analyte sensoris configured to measure an analyte selected from the group consistingof albumin, alkaline phosphatase, alanine transaminase, aspartateaminotransferase, bilirubin, blood urea nitrogen, calcium, carbondioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase,hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH,phosphorus, potassium, sodium, total protein, uric acid, a metabolicmarker and a drug.

In an embodiment of the second aspect, the system comprises at leastthree analyte sensors located within the second portion of the vascularaccess device, wherein the three sensors in combination are configuredto measure at least three analytes selected from the group consisting ofalbumin, alkaline phosphatase, alanine transaminase, aspartateaminotransferase, bilirubin, blood urea nitrogen, calcium, carbondioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase,hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH,phosphorus, potassium, sodium, total protein, uric acid, a metabolicmarker and a drug.

In an embodiment of the second aspect, the system comprises at leasteight analyte sensors located within the second portion of the vascularaccess device, wherein the three sensors in combination are configuredto measure at least eight analytes selected from the group consisting ofalbumin, alkaline phosphatase, alanine transaminase, aspartateaminotransferase, bilirubin, blood urea nitrogen, calcium, carbondioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase,hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH,phosphorus, potassium, sodium, total protein, uric acid, a metabolicmarker and a drug.

In an embodiment of the second aspect, a lumen of the second portion iswider than a lumen of the first portion.

In a third aspect, a system configured to measure at least one analytein a host is provided, the system comprising: a catheter comprising afirst portion configured for insertion into a host and a second portionconfigured to remain outside the host after insertion of the firstportion; and at least one analyte sensor located within the secondportion of the catheter, such that the at least one analyte sensor isexposed to a biological sample when the biological sample is drawn backinto the catheter to a distance of about 40 mm or less, when thecatheter is in fluid communication with a circulatory system of thehost.

In an embodiment of the third aspect, the at least one analyte sensor isexposed to the biological sample when a volume of about 300 μl or lessof the biological sample is drawn back.

In an embodiment of the third aspect, the at least one analyte sensor isexposed to the biological sample when a volume of about 200 μl or lessof the biological sample is drawn back.

In an embodiment of the third aspect, the catheter is 22 gauge orsmaller.

In an embodiment of the third aspect, the second portion comprises afluid coupler, wherein the fluid coupler is configured to releasablymate with the catheter.

In an embodiment of the third aspect, the at least one sensor isincorporated into the second portion.

In an embodiment of the third aspect, the at least one sensor is locatedon an inner surface of the second portion.

In an embodiment of the third aspect, the at least one sensor isdisposed within a lumen of the second portion.

In an embodiment of the third aspect, at least a portion of the at leastone sensor is disposed in an orientation substantially parallel to alongitudinal axis of the second portion.

In an embodiment of the third aspect, at least a portion of the at leastone sensor is disposed in an orientation substantially perpendicular toa longitudinal axis of the second portion.

In an embodiment of the third aspect, the at least one sensor comprisesan exposed electroactive surface area with a dimension substantiallyequal to a width of a lumen of the second portion.

In an embodiment of the third aspect, the exposed electroactive surfacearea intersects the lumen of the second portion.

In an embodiment of the third aspect, the second portion is configuredto provide identification information associated with a flow profile.

In an embodiment of the third aspect, the system is configured toprogram the flow profile of the flow control device in response to anautomatic receipt of the identification information.

In an embodiment of the third aspect, the identification information isprovided by a mechanical structure of the catheter.

In an embodiment of the third aspect, the identification information isprovided by electronics associated with the catheter.

In an embodiment of the third aspect, the catheter comprises at leasttwo lumens, and wherein the system is configured and arranged to infusea fluid into a first lumen of the catheter, and wherein the system isconfigured and arranged draw back a biological sample into a secondlumen of the catheter.

In an embodiment of the third aspect, the at least one analyte sensor isconfigured to measure an analyte selected from the group consisting ofalbumin, alkaline phosphatase, alanine transaminase, aspartateaminotransferase, bilirubin, blood urea nitrogen, calcium, carbondioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase,hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH,phosphorus, potassium, sodium, total protein, uric acid, a metabolicmarker and a drug.

In an embodiment of the third aspect, the system comprises at leastthree analyte sensors located within the second portion of the catheter,wherein the three sensors in combination are configured to measure atleast three analytes selected from the group consisting of albumin,alkaline phosphatase, alanine transaminase, aspartate aminotransferase,bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride,creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate,lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium,sodium, total protein, uric acid, a metabolic marker and a drug.

In an embodiment of the third aspect, the system comprises at leasteight analyte sensors located within the second portion of the catheter,wherein the eight sensors in combination are configured to measure atleast eight analytes selected from the group consisting of albumin,alkaline phosphatase, alanine transaminase, aspartate aminotransferase,bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride,creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate,lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium,sodium, total protein, uric acid, a metabolic marker and a drug.

In an embodiment of the third aspect, the system further comprises aflow control device configured to regulate exposure of the at least onesensor to a biological sample and to a solution according to a flowprofile.

In an embodiment of the third aspect, a lumen of the second portion iswider than a lumen of the first portion.

In a fourth aspect, a system configured to measure at least one analytein a biological sample of the host is provided, the system comprising: afluid coupler comprising a first end and a second end, wherein the firstend is configured to releasably mate with a connecting end of acatheter, and wherein the second end is configured to releasably matewith a tubing assembly; and at least one analyte sensor located withinthe fluid coupler such that when the fluid coupler is mated to acatheter inserted into a circulatory system of a host, the at least oneanalyte sensor is exposed to a biological sample when the biologicalsample is drawn back into the catheter to a distance of about 40 mm orless.

In an embodiment of the fourth aspect, the at least one analyte sensoris exposed to the biological sample when a volume of about 300 μl orless of the biological sample is drawn back.

In an embodiment of the fourth aspect, the at least one analyte sensoris exposed to the biological sample when a volume of about 200 μl orless of the biological sample is drawn back.

In an embodiment of the fourth aspect, the at least one analyte sensoris incorporated into the fluid coupler.

In an embodiment of the fourth aspect, the at least one analyte sensoris located on an inner surface of the fluid coupler.

In an embodiment of the fourth aspect, the at least one analyte sensoris disposed within a lumen of the fluid coupler.

In an embodiment of the fourth aspect, at least a portion of the atleast one sensor is disposed in an orientation substantially parallel toa longitudinal axis of the fluid coupler.

In an embodiment of the fourth aspect, at least a portion of the atleast one sensor is disposed in an orientation substantiallyperpendicular to a longitudinal axis of the fluid coupler.

In an embodiment of the fourth aspect, the at least one sensor comprisesan exposed electroactive surface area with a dimension substantiallyequal to a width of a lumen of the fluid coupler.

In an embodiment of the fourth aspect, the exposed electroactive surfacearea intersects the lumen of the fluid coupler.

In an embodiment of the fourth aspect, the fluid coupler is configuredto provide identification information associated with a flow profile.

In an embodiment of the fourth aspect, the system is configured toprogram the flow profile of the flow control device in response to anautomatic receipt of the identification information.

In an embodiment of the fourth aspect, the identification information isprovided by a mechanical structure of the fluid coupler.

In an embodiment of the fourth aspect, the identification information isprovided by electronics associated with the fluid coupler.

In an embodiment of the fourth aspect, the fluid coupler comprises atleast two lumens, and wherein the system is configured and arranged toinfuse a fluid into a first lumen of the fluid coupler, and wherein thesystem is configured and arranged draw back a biological sample into asecond lumen of the fluid coupler.

In an embodiment of the fourth aspect, the at least one analyte sensoris configured to measure an analyte selected from the group consistingof albumin, alkaline phosphatase, alanine transaminase, aspartateaminotransferase, bilirubin, blood urea nitrogen, calcium, carbondioxide, chloride, creatinine, glucose, gamma-glutamyl transpeptidase,hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH,phosphorus, potassium, sodium, total protein, uric acid, a metabolicmarker and a drug.

In an embodiment of the fourth aspect, the system comprises at leastthree analyte sensors located within the fluid coupler, wherein thethree sensors in combination are configured to measure at least threeanalytes selected from the group consisting of albumin, alkalinephosphatase, alanine transaminase, aspartate aminotransferase,bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride,creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate,lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium,sodium, total protein, uric acid, a metabolic marker and a drug.

In an embodiment of the fourth aspect, the system comprises at leasteight analyte sensors located within the fluid coupler, wherein thethree sensors in combination are configured to measure at least eightanalytes selected from the group consisting of albumin, alkalinephosphatase, alanine transaminase, aspartate aminotransferase,bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride,creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit, lactate,lactate dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium,sodium, total protein, uric acid, a metabolic marker and a drug.

In an embodiment of the fourth aspect, the system further comprises acatheter.

In an embodiment of the fourth aspect, the system further comprises aflow control device configured to regulate exposure of the at least onesensor to a biological sample and to a solution according to a flowprofile.

In a fifth aspect, a method for evaluating a change in a sensitivity ofan analyte sensor over a predetermined time period is provided, themethod comprising: receiving sensor data from an analyte sensor, whereinthe sensor data comprises one or more sensor analyte values measured ina biological sample of a host; intermittently calculating a sensitivityof the analyte sensor based at least in part on reference analyte data;and evaluating a change in sensitivity by evaluating a plurality oftime-spaced sensitivity calculations over a predetermined time period.

In an embodiment of the fifth aspect, the predetermined time period isless than or equal to about 30 minutes.

In an embodiment of the fifth aspect, the predetermined time period isless than or equal to about 20 minutes.

In an embodiment of the fifth aspect, the predetermined time period isless than or equal to about 10 minutes.

In an embodiment of the fifth aspect, the step of evaluating a change insensitivity comprises evaluating at least two sensitivity measurementsduring the predetermined time period.

In an embodiment of the fifth aspect, the method further comprisesaveraging and/or filtering the at least two sensitivity measurementsprior to the step of evaluating the at least two sensitivitymeasurements.

In an embodiment of the fifth aspect, the step of evaluating a change insensitivity comprises comparing the change in sensitivity with one ormore criteria.

In an embodiment of the fifth aspect, the method further comprises usinga most recent sensitivity calculation evaluated to calibrate the analytesensor when the change in sensitivity meets one or more criteria.

In an embodiment of the fifth aspect, the method further comprises notusing a most recent sensitivity calculation evaluated to calibrate theanalyte sensor when the change in sensitivity does not meet one or morecriteria.

In an embodiment of the fifth aspect, the step of intermittentlycalculating a sensitivity of the analyte sensor comprises intermittentlyreceiving a reference analyte value.

In an embodiment of the fifth aspect, the step of intermittentlyreceiving a reference analyte value comprises periodically receiving ameasured analyte concentration from a reference analyte solution.

In an embodiment of the fifth aspect, the step of intermittentlyreceiving a reference analyte value comprises receiving a referenceanalyte value obtained from an in vitro analyte monitor.

In an embodiment of the fifth aspect, the step of evaluating asensitivity is iteratively performed on the plurality of time-spacedsensitivity calculations over the predetermined time period.

In an embodiment of the fifth aspect, the predetermined time period isat least about 30 minutes.

In an embodiment of the fifth aspect, the predetermined time period isat least about 60 minutes.

In an embodiment of the fifth aspect, the predetermined time period isat least about 120 minutes.

In an embodiment of the fifth aspect, the step of evaluating asensitivity is iteratively performed on the plurality of time-spacedsensitivity calculations over the predetermined time period.

In an embodiment of the fifth aspect, the step of evaluating asensitivity comprises evaluating all sensitivity calculations over asensor session.

In an embodiment of the fifth aspect, the step of evaluating asensitivity is based at least in part on a priori sensitivityinformation.

In an embodiment of the fifth aspect, the a priori sensitivityinformation is an expected profile.

In an embodiment of the fifth aspect, the a priori sensitivityinformation defines a range of acceptable change in sensitivity.

In an embodiment of the fifth aspect, the analyte sensor comprises afirst working electrode and a second working electrode, wherein thefirst working electrode is configured to provide a first signalcomprising an analyte component and a baseline component and wherein thesecond working electrode is configured to provide a second signalcomprising a baseline component without an analyte component.

In an embodiment of the fifth aspect, the step of intermittentlycalculating a sensitivity of the analyte sensor is based at least inpart on the first signal.

In an embodiment of the fifth aspect, the step of intermittentlycalculating a sensitivity of the analyte sensor is based at least inpart on the second signal.

In an embodiment of the fifth aspect, the method further comprisessubtracting the second signal from the first signal to obtain asubtracted signal, wherein the step of intermittently calculating asensitivity of the analyte sensor is based at least in part on thesubtracted signal.

In an embodiment of the fifth aspect, the analyte sensor isintermittently exposed to a biological sample and to a referencesolution.

In an embodiment of the fifth aspect, the step of intermittentlycalculating a sensitivity of the analyte sensor is based at least inpart on a signal obtained when the analyte sensor is exposed to abiological sample.

In an embodiment of the fifth aspect, the step of intermittentlycalculating a sensitivity of the analyte sensor is based at least inpart on a signal obtained when the analyte sensor is exposed to areference solution.

In an embodiment of the fifth aspect, the step of intermittentlycalculating a sensitivity of the analyte sensor is based at least inpart on a signal obtained when the analyte sensor is exposed to abiological sample and a signal obtained when the analyte sensor isexposed to a reference solution.

In a sixth aspect, a system for evaluating a change in a sensitivity ofan analyte sensor over a predetermined time period is provided, thesystem comprising: an analyte sensor; and a computer system, wherein thecomputer system comprises: an input module configured to receive sensoranalyte data and reference analyte data, wherein the sensor datacomprises one or more sensor analyte values measured in a biologicalsample of a host and wherein the reference data comprises one or morereference analyte values; and a processor module configured tointermittently calculate a sensitivity of the analyte sensor based atleast in part on the reference analyte data and to evaluate a change insensitivity by evaluating a plurality of time-spaced sensitivitycalculations over a predetermined time period.

In an embodiment of the sixth aspect, the predetermined time period isless than or equal to about 30 minutes.

In an embodiment of the sixth aspect, the predetermined time period isless than or equal to about 20 minutes.

In an embodiment of the sixth aspect, the predetermined time period isless than or equal to about 10 minutes.

In an embodiment of the sixth aspect, the processor module is configuredto evaluate the change in sensitivity at least in part by evaluating atleast two sensitivity measurements during the predetermined time period.

In an embodiment of the sixth aspect, the processor module is furtherconfigured to average and/or filter the at least two sensitivitymeasurements prior to evaluating the at least two sensitivitymeasurements.

In an embodiment of the sixth aspect, the processor module is furtherconfigured to compare the change in sensitivity with one or morecriteria.

In an embodiment of the sixth aspect, the processor module is furtherconfigured to use a most recent sensitivity calculation evaluated tocalibrate the analyte sensor when the change in sensitivity meets one ormore criteria.

In an embodiment of the sixth aspect, the processor module is furtherconfigured to not use a most recent sensitivity calculation evaluated tocalibrate the analyte sensor when the change in sensitivity does notmeet one or more criteria.

In an embodiment of the sixth aspect, the predetermined time period isat least about 30 minutes.

In an embodiment of the sixth aspect, the predetermined time period isat least about 60 minutes.

In an embodiment of the sixth aspect, the predetermined time period isat least about 120 minutes.

In an embodiment of the sixth aspect, the processor module is configuredto iteratively evaluate a sensitivity of the plurality of time-spacedsensitivity calculations over the predetermined time period.

In an embodiment of the sixth aspect, the processor module is configuredto evaluate all sensitivity calculations over a sensor session.

In an embodiment of the sixth aspect, the processor module is configuredto evaluate a sensitivity based at least in part on a priori sensitivityinformation.

In an embodiment of the sixth aspect, the a priori sensitivityinformation is an expected profile.

In an embodiment of the sixth aspect, the a priori sensitivityinformation defines a range of acceptable change in sensitivity.

In an embodiment of the sixth aspect, the analyte sensor data comprisesa first signal comprising an analyte component and a baseline componentand a second signal comprising a baseline component without an analytecomponent.

In an embodiment of the sixth aspect, the processor module is configuredto calculate a sensitivity of the analyte sensor based at least in parton the first signal.

In an embodiment of the sixth aspect, the processor module is configuredto calculate a sensitivity of the analyte sensor based at least in parton the second signal.

In an embodiment of the sixth aspect, the processor module is furtherconfigured to calculate a sensitivity of the analyte sensor based atleast in part on a subtracted signal, wherein the subtracted signalcomprises the second signal subtracted from the first signal.

In an embodiment of the sixth aspect, the system further comprises aflow control device configured to intermittently expose the sensor tothe biological sample and to a reference solution.

In an embodiment of the sixth aspect, the processor module is configuredto intermittently calculate a sensitivity of the analyte sensor based atleast in part on a signal obtained when the analyte sensor is exposed tothe biological sample.

In an embodiment of the sixth aspect, the processor module is configuredto intermittently calculate a sensitivity of the analyte sensor based atleast in part on a signal obtained when the analyte sensor is exposed tothe reference solution.

In an embodiment of the sixth aspect, the processor module is configuredto intermittently calculate a sensitivity of the analyte sensor based ona signal obtained when the analyte sensor is exposed to the biologicalsample and a signal obtained when the analyte sensor is exposed to thereference solution.

In a seventh aspect, a method for performing a diagnostic of an analytesensor system is provided, comprising: providing a sensor systemcomprising an analyte sensor and a flow control device configured tointermittently expose the analyte sensor to a biological sample and aninfusion solution, wherein the analyte sensor comprises: a first workingelectrode configured to provide a first signal comprising an analytecomponent and a baseline component; and a second working electrodeconfigured to provide a second signal comprising a baseline componentsubstantially without an analyte component; and evaluating the sensorsystem based at least in part on the second signal.

In an embodiment of the seventh aspect, the second signal comprises asignal waveform, and wherein the step of evaluating the sensor systemcomprises evaluating the signal waveform for at least one of an expectedshape and a pattern when the analyte sensor is exposed to at least oneof the biological sample and the infusion solution.

In an embodiment of the seventh aspect, the step of evaluating thesignal waveform comprises evaluating at least one of a similarity and acorrelation between the signal waveform and a waveform template.

In an embodiment of the seventh aspect, the waveform template is basedat least in part on a priori information.

In an embodiment of the seventh aspect, the waveform template is basedat least in part on a signal waveform measured by the sensor system.

In an embodiment of the seventh aspect, the step of evaluating at leastone of a similarity and a correlation of the signal waveform to awaveform template comprises performing a correlation waveform analysis.

In an embodiment of the seventh aspect, the method further comprisesupdating the waveform template when at least one of the similarity andthe correlation between the signal waveform and the waveform templatemeets one or more criteria.

In an embodiment of the seventh aspect, the method further comprisesdetecting a level of interferent in the biological sample, wherein thewaveform template is updated when the level of interferent meets one ormore criteria.

In an embodiment of the seventh aspect, the step of evaluating thesignal waveform comprises evaluating a monotonicity of the signalwaveform.

In an embodiment of the seventh aspect, the step of evaluating amonotonicity of the signal waveform comprises performing a correlationwaveform analysis of the signal waveform with the waveform template.

In an embodiment of the seventh aspect, the step of evaluating amonotonicity of the signal waveform comprises performing a time-seriesanalysis.

In an embodiment of the seventh aspect, the step of evaluating thesensor system comprises detecting an interferent by evaluating at leastone of an amplitude, a change in amplitude, a signal waveform, and achange in a signal waveform of the second signal when the sensor isexposed to the biological sample.

In an embodiment of the seventh aspect, the step of detecting aninterferent is further based at least in part on a calibrated analytevalue.

In an embodiment of the seventh aspect, the method further comprisescontrolling a display of the sensor system based at least in part on alevel of interferent detected on the second signal.

In an embodiment of the seventh aspect, the method further comprisesprocessing the first signal and the second signal to obtain a subtractedsignal, wherein the step of processing is based at least in part a levelof interferent of the sensor system.

In an embodiment of the seventh aspect, the method further comprisesdetermining a level of reliability of the sensor system by comparing atleast one of an amplitude, a change in amplitude, a signal waveform, anda change in a signal waveform of the second signal to one or morecriteria.

In an embodiment of the seventh aspect, the method further comprisescontrolling a display of the sensor system based at least in part on thelevel of reliability of the sensor system.

In an embodiment of the seventh aspect, the step of evaluating comprisesdetermining a success of a biological sample draw-back from a host'scirculatory system to the analyte sensor.

In an embodiment of the seventh aspect, the method further comprisesdisplaying an analyte value measured during the biological sampledraw-back in response to a determination of a successful biologicalsample draw-back.

In an embodiment of the seventh aspect, the step of evaluating comprisesdetermining a success of infusing the infusion solution such that thebiological sample is washed from the sensor.

In an embodiment of the seventh aspect, the step of determining asuccess of infusing comprises displaying an analyte value measured inthe biological sample after infusing the infusion solution in responseto a determination of a successful infusion.

In an eighth aspect, a system for performing a diagnostic of an analytesensor system is provided, comprising: an analyte sensor systemcomprising a sensor, wherein the analyte sensor comprises a firstworking electrode configured to provide a first signal comprising ananalyte component and a baseline component and a second workingelectrode configured to provide a second signal comprising a baselinecomponent substantially without an analyte component; a flow controldevice configured to intermittently expose the analyte sensor to abiological sample and an infusion solution; and a processor moduleconfigured to evaluate the analyte sensor system based at least in parton the second signal.

In an embodiment of the eighth aspect, the second signal comprises asignal waveform, and wherein the processor module is configured toevaluate the signal waveform for at least one of an expected shape and apattern when the analyte sensor is exposed to at least one of thebiological sample and the infusion solution.

In an embodiment of the eighth aspect, the processor module isconfigured to evaluate the signal waveform by evaluating at least one ofa similarity and a correlation between the signal waveform and awaveform template.

In an embodiment of the eighth aspect, the waveform template is based atleast in part on a priori information.

In an embodiment of the eighth aspect, the waveform template is based atleast in part on a signal waveform measured by the analyte sensorsystem.

In an embodiment of the eighth aspect, the processor module isconfigured to evaluate at least one of a similarity and a correlationbetween the signal waveform and the waveform template by performing acorrelation waveform analysis.

In an embodiment of the eighth aspect, the processor module is furtherconfigured to update the waveform template when at least one of asimilarity and a correlation between the signal waveform and thewaveform template meets one or more criteria.

In an embodiment of the eighth aspect, the processor module isconfigured to detect a level of an interferent in the biological sample,and wherein the processor module is further configured to update thewaveform template when the level of the interferent meets one or morecriteria.

In an embodiment of the eighth aspect, the processor module isconfigured to evaluate the signal waveform by evaluating a monotonicityof the signal waveform.

In an embodiment of the eighth aspect, the processor module isconfigured to evaluate a monotonicity at least in part by performing acorrelation waveform analysis of the signal waveform with a waveformtemplate.

In an embodiment of the eighth aspect, the processor module isconfigured evaluate a monotonicity at least in part by performing atime-series analysis.

In an embodiment of the eighth aspect, the processor module isconfigured to detect an interferent at least in part by evaluating atleast one of an amplitude, a change in amplitude, a signal waveform, anda change in a signal waveform of the second signal when the sensor isexposed to a biological sample.

In an embodiment of the eighth aspect, the processor module isconfigured to detect an interferent at least in part by evaluating acalibrated analyte value with one or more criteria.

In an embodiment of the eighth aspect, the one or more criteria arebased on physiological feasibility.

In an embodiment of the eighth aspect, the processor module isconfigured to control a display of the analyte sensor system based atleast in part on a level of an interferent detected on the secondsignal.

In an embodiment of the eighth aspect, the processor module is furtherconfigured to process the first signal and the second signal to obtain asubtracted signal based at least in part on a level of an interferent ofthe sensor system.

In an embodiment of the eighth aspect, the processor module isconfigured evaluate a level of reliability of the sensor system at leastin part by comparing at least one of an amplitude, a change inamplitude, a signal waveform, and a change in a signal waveform of thesecond signal to one or more criteria.

In an embodiment of the eighth aspect, the processor module isconfigured to control a display of the sensor system based at least inpart on a level of reliability of the sensor system.

In an embodiment of the eighth aspect, processor module is furtherconfigured determine a success of drawing-back of a biological samplefrom a host's circulatory system to the analyte sensor, based at leastin part on the evaluation of the analyte sensor system.

In an embodiment of the eighth aspect, the processor module isconfigured to display an analyte value measured during the biologicalsample draw-back, in response to a determination of a successfuldraw-back of the biological sample.

In an embodiment of the eighth aspect, the processor module is furtherconfigured to determine a success of infusing the infusion solution suchthat the biological sample is washed from the sensor.

In an embodiment of the eighth aspect, the processor module isconfigured to display an analyte value measured in the biological sampleafter infusing the infusion solution, in response to a determination ofa successful infusion.

In a ninth aspect, a method for determining a stability of an analytesensor is provided, the method comprising: exposing an analyte sensor toa biological sample, wherein the analyte sensor comprises a firstworking electrode that measures an analyte component and a baselinecomponent and a second working electrode that measures a baselinecomponent substantially without an analyte component; receiving sensordata from the analyte sensor, wherein the sensor data comprises firstsensor data associated with the first working electrode and secondsensor data associated with the second working electrode; anddetermining a stability of the analyte sensor based at least in part onthe second sensor data.

In an embodiment of the ninth aspect, the second sensor data comprises aplurality of time spaced data points, and wherein the step ofdetermining a stability of the analyte sensor comprises evaluating achange in amplitude of two or more of the plurality of time spaced datapoints.

In an embodiment of the ninth aspect, the step of exposing the analytesensor to a biological sample comprises intermittently exposing theanalyte sensor to a biological sample and to an infusion solution.

In an embodiment of the ninth aspect, the step of evaluating comprisescomparing a plurality of time spaced points measured when the analytesensor is exposed to the biological sample.

In an embodiment of the ninth aspect, the step of evaluating comprisescomparing a first point measured when the analyte sensor is exposed tothe biological sample to a second point measured when the analyte sensoris exposed to the infusion solution.

In an embodiment of the ninth aspect, the step of evaluating comprisesevaluating transient information of the second sensor data during a stepchange from exposure of the sensor to the infusion solution to exposureof the sensor to the biological sample.

In an embodiment of the ninth aspect, the method further comprisesdetermining a predetermined level of stability when a change in anamplitude of the second sensor data meets one or more criteria.

In an embodiment of the ninth aspect, the method further comprisescontrolling a display associated with the analyte sensor system inresponse to the determination of the predetermined level of stability.

In an embodiment of the ninth aspect, the step of controlling a displaycomprises providing at least one of a numeric estimated analyte value, adirectional trend of analyte concentration, and a graphicalrepresentation of a plurality of estimated analyte values.

In an embodiment of the ninth aspect, the step of controlling a displaycomprises requesting reference analyte data.

In an embodiment of the ninth aspect, the step of determining astability of the analyte sensor is performed during a predetermined timeperiod.

In an embodiment of the ninth aspect, the step of determining astability of the analyte sensor is performed after a predetermined timeperiod.

In an embodiment of the ninth aspect, the method further comprisesrepeating the step of determining a stability, wherein the step isconducted after a system re-start.

In an embodiment of the ninth aspect, the analyte sensor is a glucosesensor.

In a tenth aspect, a system for determining a stability of an analytesensor is provided, the system comprising: an analyte sensor; and acomputer system, the computer system comprising: an input moduleoperatively connected to the analyte sensor and configured to receivesensor data from an analyte sensor, wherein the analyte sensor comprisesa first working electrode configured to provide first sensor datacomprising an analyte component and a baseline component and a secondworking electrode configured to provide second sensor data comprising abaseline component substantially without an analyte component; and aprocessor module configured to determine a stability of the analytesensor based at least in part on the second sensor data.

In an embodiment of the tenth aspect, the processor module is configuredto determine a stability of the analyte sensor at least in part byevaluating a change in amplitude of a plurality of time spaced pointsfrom the second sensor data.

In an embodiment of the tenth aspect, the system further comprises aflow control device configured and arranged to intermittently expose theanalyte sensor to a biological sample and to an infusion solution.

In an embodiment of the tenth aspect, the processor module is configuredto evaluate the change in amplitude at least in part by comparing aplurality of time spaced points from the second sensor data measuredwhen the analyte sensor is exposed to the biological sample.

In an embodiment of the tenth aspect, the processor module is configuredto evaluate the change in amplitude at least in part by comparing afirst point measured when the analyte sensor is exposed to thebiological sample to a second point measured when the analyte sensor isexposed to the infusion solution.

In an embodiment of the tenth aspect, the processor module is configuredto evaluate the change in amplitude at least in part by evaluatingtransient information of the second sensor data during a step changefrom exposure of the sensor to the infusion solution to exposure of thesensor to the biological sample.

In an embodiment of the tenth aspect, the processor module is configuredto determine a level of stability when a change in amplitude of aplurality of time spaced points from the second sensor data meets one ormore criteria.

In an embodiment of the tenth aspect, the processor module is configuredto control a display of calibrated sensor based at least in part on thelevel of stability.

In an embodiment of the tenth aspect, the calibrated sensor datacomprises at least one of a numeric estimated analyte value, adirectional trend of analyte concentration, and a graphicalrepresentation of a plurality of estimated analyte values.

In an embodiment of the tenth aspect, the processor module is configuredto request reference analyte data based at least in part on the level ofstability.

In an embodiment of the tenth aspect, the processor module is furtherconfigured to determine a stability of the analyte sensor during apredetermined time period.

In an embodiment of the tenth aspect, processor module is furtherconfigured to determine a stability of the analyte sensor after apredetermined time period.

In an embodiment of the tenth aspect, the analyte sensor is a glucosesensor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of one embodiment of an analyte sensorsystem, including a vascular access device (e.g., a catheter), a sensor,a fluid connector, and a protective sheath.

FIG. 1B is a side view of the analyte sensor system of FIG. 1A, showingthe protective sheath removed.

FIG. 1C ₁ is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 1C ₂ is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 1D is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 1E is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 1F is a schematic an analyte sensor system in another embodiment,including a vascular access device, a sensor, a fluid connector, and aprotective sheath.

FIG. 1G is an exploded view of the analyte sensor system of FIG. 1F.

FIG. 1H is a cut-away view of the analyte sensor system of FIG. 1F.

FIG. 1J is a magnified view of the encircled portion of the analytesensor system of FIG. 1H.

FIG. 1K is a cut-away view of an analyte sensor system in anotherembodiment.

FIG. 1L is a cut-away view of an analyte sensor system in anotherembodiment.

FIG. 1M is a cut-away view of an analyte sensor system in anotherembodiment.

FIG. 2A is a perspective view of another embodiment of the analytesensor system, including a catheter with a sensor integrally formedthereon.

FIG. 2B is a perspective view of the analyte sensor system of FIG. 2A.

FIG. 2C is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative configuration of an embodiment having threeelectrodes disposed on the catheter.

FIG. 2D is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative configuration of an embodiment having threeelectrodes disposed on the catheter.

FIG. 2E is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative embodiment having two electrodes disposed onthe catheter.

FIG. 2F is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative embodiment having one electrode disposed onthe catheter.

FIG. 2G is a cross-section of analyte sensor system in one embodiment,including a plurality of analyte sensors disposed within the connectorof a catheter.

FIG. 2H is a cross-section of analyte sensor system in one embodiment,including a plurality of analyte sensors disposed within a fluidcoupler, such as but not limited to a connector, a valve, and a Leurlock.

FIG. 2I is a cross-section of analyte sensor system of FIG. 2H, takenalong line 2I-2I.

FIG. 2J is a cross-section of analyte sensor system of FIG. 2H, takenalong line 2I-2I.

FIG. 2K is a cross-section of analyte sensor system of FIG. 2H, takenalong line 2I-2I.

FIG. 2L is a cross-section of analyte sensor system of FIG. 2H, takenalong line 2I-2I.

FIG. 2M is a side view schematic of an analyte sensor system in anotherembodiment, including a plurality of electrodes disposed in a fluidcoupler.

FIG. 2N is a schematic of an analyte sensor system in yet anotherembodiment, including a fluid coupler having a plurality of lumens, eachof which includes an analyte sensor.

FIG. 2O is a schematic illustrating a method of manufacturing theanalyte sensor system of FIG. 2M, in one embodiment.

FIG. 2P is a schematic illustrating a method of manufacturing theanalyte sensor system of FIG. 2M, in another embodiment.

FIG. 2Q is a side view schematic of an analyte sensor system, includinga fluid coupler including a plurality of sensor electrodes disposedtherein, in one embodiment.

FIG. 2R is a cross-sectional schematic of an analyte sensor system,including a fluid coupler including a plurality of sensor electrodesdisposed therein, in another embodiment.

FIG. 2S is a side view schematic of an analyte sensor system, includinga fluid coupler including a plurality of sensor electrodes disposedtherein, in still another embodiment.

FIG. 3A is a perspective view of a first portion of one embodiment of ananalyte sensor.

FIG. 3B is a perspective view of a second portion of the analyte sensorof FIG. 3A.

FIG. 3C is a cross section of the analyte sensor of FIG. 3B, taken online C-C.

FIG. 3D is a cross-sectional schematic view of a sensing region of adual-electrode continuous analyte sensor in one embodiment wherein anactive enzyme of an enzyme domain is positioned over the first workingelectrode but not over the second working electrode.

FIG. 3E is a perspective view of a dual-electrode continuous analytesensor in one embodiment.

FIG. 3F is a schematic illustrating metabolism of glucose by GlucoseOxidase (GOx) and one embodiment of a diffusion barrier D thatsubstantially prevents the diffusion of H₂O₂ produced on a first side ofthe sensor (e.g., from a first working electrode that has active GOx) toa second side of the sensor (e.g., to the second working electrode thatlacks active GOx).

FIG. 3G is a two-dimensional schematic of a dual-electrode sensor in oneembodiment, illustrating the sensor's first and second electroactivesurfaces (of the first and second working electrodes, respectively)beneath a sensor membrane, wherein noise-causing species produced by aplurality of point sources can impinge upon an electroactive surface.

FIG. 3H is a two-dimensional schematic of a dual-electrode sensor in oneembodiment, illustrating the sensor's first and second electroactivesurfaces (of the first and second working electrodes, respectively)beneath a sensor membrane, wherein noise from a single point source(e.g., a cell) can impinge upon both electroactive surfaces.

FIG. 3I is a cross-sectional schematic illustrating a dual-electrodesensor, in one embodiment, including a physical diffusion barrier.

FIG. 3J is a graph illustrating signal response of the electrodes of adual-electrode sensor, in one embodiment.

FIG. 3K is a graph illustrating signal response of the electrodes of adual-electrode sensor, in one embodiment.

FIG. 4 is a graph illustrating in vivo function of an analyte sensorsystem of the embodiment shown in FIG. 1A.

FIG. 5 is a graph illustrating in vivo function of an analyte sensorsystem of the embodiment shown in FIG. 1A.

FIG. 6 is a schematic of an integrated sensor system.

FIG. 7 is a block diagram of an integrated sensor system

FIGS. 8A through 8C are schematic illustrations of a flow control devicein one exemplary embodiment, including is relative movement/positionsand the consequential effect on the flow of fluids through thesensor/catheter inserted in a host.

FIG. 9 is a cut-away illustration of one exemplary embodiment of acatheter implanted in a host's vessel.

FIG. 10A is a schematic illustrating one exemplary embodiment of a flowcontrol device and tubing assembly.

FIG. 10B is a schematic illustrating another exemplary embodiment of aflow control device and tubing assembly.

FIG. 10C is a schematic illustrating another exemplary embodiment of aflow control device with installed tubing assembly, wherein the valve isin a gravity flow position.

FIG. 10D is a schematic illustrating another exemplary embodiment of aflow control device with installed tubing assembly, wherein the valve isin a controlled-flow position.

FIG. 10E is a graph illustrating an exemplary flow profile, in oneembodiment.

FIG. 11 is a graph that schematically illustrates a signal producedduring exposure of the sensor to a step change in analyte concentration,in one exemplary embodiment.

FIG. 12 is a graph that schematically illustrates a derivative of thestep response shown in FIG. 9.

FIG. 13 is a graph that illustrates level vs. rate for a plurality oftime-spaced signals associated with exposure of the sensor to biologicalsamples of unknown or uncalibrated analyte concentration.

FIG. 14 is a flow chart illustrating sensor sensitivity evaluation, inone embodiment.

FIG. 15 is a flow chart illustrating sensor stability evaluation, in oneembodiment.

FIG. 16 is a flow chart illustrating system diagnostics, in oneembodiment.

FIG. 17 is a graphical representation showing exemplary glucose sensordata and corresponding blood glucose values over time in a pig.

FIG. 18 is a graphical representation showing exemplary calibratedglucose sensor data (test) and corresponding blood glucose values (YSIcontrol) over time in a human.

FIG. 19A is a graph that illustrates an in vivo signal (counts) detectedfrom a dual-electrode sensor, in one embodiment, implanted in anon-diabetic human host.

FIG. 19B is a graph that illustrates an in vivo signal (counts) detectedfrom a dual-electrode, in another embodiment, implanted in anon-diabetic human host.

FIG. 20A is a graph that illustrates an in vivo signal (counts) detectedfrom a dual-electrode, in one embodiment, implanted in a non-diabetichuman host.

FIG. 20B is a graph that illustrates an in vivo signal (counts) detectedfrom a dual-electrode, in another embodiment, implanted in anon-diabetic human host.

FIG. 21A is a graph that illustrates an in vivo glucose values detectedfrom a dual-electrode, in another embodiment, implanted in anon-diabetic porcine host.

FIG. 21B is a Clark Error Grid graph of the data of FIG. 21A.

FIG. 22 is a graph of a signal waveform generated during a successfulinfusion of the reference solution into the host versus the adaptivecalibration waveform template.

FIG. 23 is a graph of a signal waveform generated during an unsuccessfulinfusion of the reference solution into the host versus the adaptivecalibration waveform template.

FIG. 24 is a graph of the signals generated from the plus-enzyme workingelectrode and from the no-enzyme working electrode illustrating sensorstabilization.

FIG. 25 is a graph illustrating sensor sensitivity over time.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the preferred embodiments.

DEFINITIONS

In order to facilitate an understanding of the preferred embodiments, anumber of terms are defined below.

The term “analyte” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a substance or chemical constituent in abiological sample (e.g., bodily fluids, including, blood, serum, plasma,interstitial fluid, cerebral spinal fluid, lymph fluid, ocular fluid,saliva, oral fluid, urine, excretions or exudates). Analytes can includenaturally occurring substances, artificial substances, metabolites,and/or reaction products. In some embodiments, the analyte formeasurement by the sensing regions, devices, and methods is albumin,alkaline phosphatase, alanine transaminase, aspartate aminotransferase,bilirubin, blood urea nitrogen, calcium, CO₂, chloride, creatinine,glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactatedehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium,total protein, uric acid, metabolic markers, and drugs. However, otheranalytes are contemplated as well, including but not limited toacetaminophen, dopamine, ephedrine, terbutaline, ascorbate, uric acid,oxygen, d-amino acid oxidase, plasma amine oxidase, xanthine oxidase,NADPH oxidase, alcohol oxidase, alcohol dehydrogenase, pyruvatedehydrogenase, diols, Ros, NO, bilirubin, cholesterol, triglycerides,gentisic acid, ibuprophen, L-Dopa, methyl dopa, salicylates,tetracycline, tolazamide, tolbutamide, acarboxyprothrombin;acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase;albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactiveprotein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholicacid; chloroquine; cholesterol; cholinesterase; conjugated 1-βhydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MMisoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine;dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcoholdehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne/Beckermuscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A,hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F,D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1,Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax,sexual differentiation, 21-deoxycortisol); desbutylhalofantrine;dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocytearginase; erythrocyte protoporphyrin; esterase D; fattyacids/acylglycines; free β-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β);lysozyme; mefloquine; netilmicin; phenobarbitone; phenyloin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins, and hormones naturally occurring in blood or interstitialfluids can also constitute analytes in certain embodiments. The analytecan be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte can be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body can also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC),homovanillic acid (HVA), 5-hydroxytryptamine (5HT), histamine, AdvancedGlycation End Products (AGEs) and 5-hydroxyindoleacetic acid (FHIAA).

The term “antegrade” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and are not to be limited to a special or customized meaning), andrefers without limitation to orientation (e.g., of a catheter) with thedirection of blood flow.

The term “baseline,” “noise” and “background signal” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and refers without limitation to acomponent of an analyte sensor signal that is not related to the analyteconcentration. In one example of a glucose sensor, the baseline iscomposed substantially of signal contribution due to factors other thanglucose (for example, interfering species, non-reaction-related hydrogenperoxide, or other electroactive species with an oxidation/reductionpotential that overlaps with hydrogen peroxide). In some embodimentswherein a calibration is defined by solving for the equation y=mx+b, thevalue of b represents the baseline, or background, of the signal.

The terms “baseline and/or sensitivity shift,” “baseline and/orsensitivity drift,” “shift,” and “drift” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to a change in thebaseline and/or sensitivity of the sensor signal over time. While theterm “shift” generally refers to a substantially distinct change over arelatively short time period, and the term “drift” generally refers to asubstantially gradual change over a relatively longer time period, theterms can be used interchangeably and can also be generally referred toas “change” in baseline and/or sensitivity.

The term “biological sample” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a sample of a host body, forexample, blood, serum, plasma, interstitial fluid, cerebral spinalfluid, lymph fluid, ocular fluid, saliva, oral fluid, urine, sweat,excretions, exudates, and the like.

The term “blood chemistry analysis device” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refers without limitation to a device thatmeasures a variety of blood components, characteristics or analytestherein. In one embodiment, a blood chemistry analysis deviceperiodically withdraws an aliquot of blood from the host, measuresglucose, O₂, CO₂, PCO₂, PO₂, potassium, sodium, pH, lactate, urea,bilirubin, creatinine, hematocrit, various minerals, and/or variousmetabolites, and the like, and returns the blood to the host'scirculatory system. A variety of devices exist for testing various bloodproperties/analytes at the bedside, such as but not limited to the bloodgas and chemistry devices manufactured by Via Medical (Austin, Tex.,USA).

The term “blood pressure monitor” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to an instrument for monitoringthe blood pressure of a human or other animal. For example, a bloodpressure monitor can be an invasive blood pressure monitor, whichperiodically monitors the host's blood pressure via a peripheral artery,using a blood pressure transducer, such as but not limited to adisposable blood pressure transducer. Utah Medical Products Inc.(Midvale, Utah, USA) produces a variety of DELTRAN® Brand disposableblood pressure transducers that are suitable for use with variousembodiments disclosed herein.

The term “calibration” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the relationship and/orprocess of determining the relationship between the sensor data and thecorresponding reference data, which can be used to convert sensor datainto values substantially equivalent to the reference data. In someembodiments, namely, in continuous analyte sensors, calibration can beupdated or recalibrated over time if changes in the relationship betweenthe sensor data and reference data occur, for example, due to changes insensitivity, baseline, transport, metabolism, and the like.

The term “casting” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a process where a fluid material is appliedto a surface or surfaces and allowed to cure or dry. The term is broadenough to encompass a variety of coating techniques, for example, usinga draw-down machine (i.e., drawing-down), dip coating, spray coating,spin coating, and the like.

The term “catheter” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and are not to be limited to a special or customized meaning), andrefers without limitation to a tube that can be inserted into a host'sbody (e.g., cavity, duct or vessel). In some circumstances, cathetersallow drainage or injection of fluids or access by medical instrumentsor devices. In some embodiments, a catheter is a thin, flexible tube(e.g., a “soft” catheter). In alternative embodiments, the catheter canbe a larger, solid tube (e.g., a “hard” catheter). The term “cannula” isinterchangeable with the term “catheter” herein.

The term “coaxial” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to having a common axis, having coincidentaxes or mounted on concentric shafts.

The term “constant analyte” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to an analyte that remainsrelatively constant over a time period, for example over an hour to aday as compared to other variable analytes. For example, in a personwith diabetes, oxygen and urea may be relatively constant analytes inparticular tissue compartments relative to glucose, which is known tooscillate between about 40 and 400 mg/dL during a 24-hour cycle.Although analytes such as oxygen and urea are known to oscillate to alesser degree, for example due to physiological processes in a host,they are substantially constant, relative to glucose, and can bedigitally filtered, for example low pass filtered, to minimize oreliminate any relatively low amplitude oscillations. Constant analytesother than oxygen and urea are also contemplated.

The terms “constant noise” and “constant background” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and it is not to be limited to aspecial or customized meaning), and refer without limitation to thecomponent of the background signal that remains relatively constant overtime. For example, certain electroactive compounds found in the humanbody are relatively constant factors (e.g., baseline of the host'sphysiology) and do not significantly adversely affect accuracy of thecalibration of the glucose concentration (e.g., they can be relativelyconstantly eliminated using the equation y=mx+b). In some circumstances,constant background noise can slowly drift over time (e.g., increases ordecreases), however this drift need not adversely affect the accuracy ofa sensor, for example, because a sensor can be calibrated andre-calibrated and/or the drift measured and compensated for.

The terms “continuous” and “continuously” as used herein are broadterms, and are to be given their ordinary and customary meanings to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to thecondition of being marked by substantially uninterrupted extension inspace, time or sequence. In one embodiment, an analyte concentration ismeasured continuously or continually, for example at time intervalsranging from fractions of a second up to, for example, about 1, 2, 5,10, 15, 20, 30, 40, 50 or 60 minutes, or longer. It should be understoodthat continuous glucose sensors generally continually measure glucoseconcentration without required user initiation and/or interaction foreach measurement, such as described with reference to U.S. Pat. No.6,001,067, for example. These terms include situations wherein data gapscan exist (e.g., when a continuous glucose sensor is temporarily notproviding data).

The term “continuous (or continual) analyte sensing” as used herein is abroad term, and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and refers without limitation to theperiod in which monitoring of analyte concentration is continuously,continually, and or intermittently (regularly or irregularly) performed,for example, about every 5 to 10 minutes.

The term “count” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a unit of measurement of a digital signal.For example, a raw data stream or raw data signal measured in counts isdirectly related to a voltage (for example, converted by an A/Dconverter), which is directly related to current from the workingelectrode. In some embodiments, the terms can refer to data that hasbeen integrated or averaged over a time period (e.g., 5 minutes).

The terms “coupling” and “operatively coupling” as used herein are broadterms, and are to be given their ordinary and customary meanings to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to ajoining or linking together of two or more things, such as two parts ofa device or two devices, such that the things can function together. Inone example, two containers can be operatively coupled by tubing, suchthat fluid can flow from one container to another. Coupling does notimply a physical connection. For example, a transmitter and a receivercan be operatively coupled by radio frequency (RF)transmission/communication.

The term “diffusion barrier” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning) and refers without limitation to something that obstructs therandom movement of compounds, species, atoms, molecules, or ions fromone site in a medium to another. In some embodiments, a diffusionbarrier is structural, such as a wall that separates two workingelectrodes and substantially prevents diffusion of a species from oneelectrode to the other. In some embodiments, a diffusion barrier isspatial, such as separating working electrodes by a distancesufficiently large enough to substantially prevent a species at a firstelectrode from affecting a second electrode. In other embodiments, adiffusion barrier can be temporal, such as by turning the first andsecond working electrodes on and off, such that a reaction at a firstelectrode will not substantially affect the function of the secondelectrode.

The term “dip coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to coating, which involvesdipping an object or material into a liquid coating substance.

The term “distal to” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the spatial relationship between variouselements in comparison to a particular point of reference. In general,the term indicates an element is located relatively far from thereference point than another element.

The term “domain” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a region of the membrane system that can bea layer, a uniform or non-uniform gradient (for example, an anisotropicregion of a membrane), or a portion of a membrane.

The term “electrochemical break-in” as used herein is a broad term, andis to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to the time, after invitro and/or in vivo settling of the current output from the sensorfollowing the application of the potential to the sensor.

The term “electrochemically reactive surface” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a surface where anelectrochemical reaction takes place. For example, a working electrodemeasures hydrogen peroxide produced by the enzyme-catalyzed reaction ofthe analyte detected, which reacts to create an electric current.Glucose analyte can be detected utilizing glucose oxidase, whichproduces H₂O₂ as a byproduct. H₂O₂ reacts with the surface of theworking electrode, producing two protons (2H⁺), two electrons (2e⁻) andone molecule of oxygen (O₂), which produces the electronic current beingdetected.

The terms “electronic connection,” “electrical connection,” “electricalcontact” as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), and referwithout limitation to any connection between two electrical conductorsknown to those in the art. In one embodiment, electrodes are inelectrical connection with the electronic circuitry of a device.

The terms “electronics” and “sensor electronics” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation toelectronics operatively coupled to the sensor and configured to measure,process, receive, and/or transmit data associated with a sensor. In someembodiments, the electronics include at least a potentiostat thatprovides a bias to the electrodes and measures a current to provide theraw data signal. The electronics are configured to calculate at leastone analyte sensor data point. For example, the electronics can includea potentiostat, A/D converter, RAM, ROM, and/or transmitter. In someembodiments, the potentiostat converts the raw data (e.g., raw counts)collected from the sensor and converts it to a value familiar to thehost and/or medical personnel. For example, the raw counts from aglucose sensor can be converted to milligrams of glucose per deciliterof blood (e.g., mg/dl). In some embodiments, the sensor electronicsinclude a transmitter that transmits the signals from the potentiostatto a receiver (e.g., a remote analyzer, such as but not limited to aremote analyzer unit), where additional data analysis and glucoseconcentration determination can occur.

The term “ex vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a portion of a device (forexample, a sensor) adapted to remain and/or exist outside of a livingbody of a host.

The term “fluid communication” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to two or more components (e.g.,things such as parts of a body or parts of a device) functionally linkedsuch that fluid can move from one component to another. These terms donot imply directionality.

The term “GOx” as used herein is a broad term, and is to be given theirordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to the enzyme Glucose Oxidase (e.g., GOx is anabbreviation).

The term “helix” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to a spiral or coil, or something in the formof a spiral or coil (e.g. a corkscrew or a coiled spring). In oneexample, a helix is a mathematical curve that lies on a cylinder or coneand makes a constant angle with the straight lines lying in the cylinderor cone. A “double helix” is a pair of parallel helices intertwinedabout a common axis, such as but not limited to that in the structure ofDNA.

The term “host” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to animals or plants, for example humans.

The term “hyperglycemia” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to a condition in which anexcessive or high amount of glucose exists in a host. Hyperglycemia isone of the classic symptoms of diabetes mellitus. Non-diabetichyperglycemia is associated with obesity and certain eating disorders,such as bulimia nervosa. Hyperglycemia is also associated with otherdiseases (or medications) affecting pancreatic function, such aspancreatic cancer. Hyperglycemia is also associated with poor medicaloutcomes in a variety of clinical settings, such as intensive orcritical care settings.

The term “hypoglycemia” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to a condition in which alimited or low amount of glucose exists in a host. Hypoglycemia canproduce a variety of symptoms and effects but the principal problemsarise from an inadequate supply of glucose as fuel to the brain,resulting in impairment of function (neuroglycopenia). Derangements offunction can range from vaguely “feeling bad” to coma, and (rarely)permanent brain damage or death.

The terms “inactive enzyme” or “inactivated enzyme” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and it is not to be limited to aspecial or customized meaning), and refer without limitation to anenzyme (e.g., glucose oxidase, GOx) that has been rendered inactive(e.g., “killed” or “dead”) and has no enzymatic activity. Enzymes can beinactivated using a variety of techniques known in the art, such as butnot limited to heating, freeze-thaw, denaturing in organic solvent,acids or bases, cross-linking, genetically changing enzymaticallycritical amino acids, and the like. In some embodiments, a solutioncontaining active enzyme can be applied to the sensor, and the appliedenzyme subsequently inactivated by heating or treatment with aninactivating solvent.

The term “indwell” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and are not to be limited to a special or customized meaning), andrefers without limitation to reside within a host's body. Some medicaldevices can indwell within a host's body for various lengths of time,depending upon the purpose of the medical device, such as but notlimited to a few hours, days, or weeks, to months, years, or even thehost's entire lifetime. In one exemplary embodiment, an arterialcatheter may indwell within the host's artery for a few hours, days, aweek, or longer, such as but not limited to the host's perioperativeperiod (e.g., from the time the host is admitted to the hospital to thetime he is discharged).

The terms “insulative properties,” “electrical insulator” and“insulator” as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning) and referswithout limitation to the tendency of materials that lack mobile chargesto prevent movement of electrical charges between two points. In oneexemplary embodiment, an electrically insulative material may be placedbetween two electrically conductive materials, to prevent movement ofelectricity between the two electrically conductive materials. In someembodiments, the terms refer to a sufficient amount of insulativeproperty (e.g., of a material) to provide a necessary function(electrical insulation). The terms “insulator” and “non-conductivematerial” can be used interchangeably herein.

The terms “integral,” “integrally,” “integrally formed,” integrallyincorporated,” “unitary” and “composite” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and they are not to be limited to a specialor customized meaning), and refer without limitation to the condition ofbeing composed of essential parts or elements that together make awhole. The parts are essential for completeness of the whole. In oneexemplary embodiment, at least a portion (e.g., the in vivo portion) ofthe sensor is formed from at least one platinum wire at least partiallycovered with an insulative coating, which is at least partiallyhelically wound with at least one additional wire, the exposedelectroactive portions of which are covered by a membrane system (seedescription of FIG. 1B or 9B); in this exemplary embodiment, eachelement of the sensor is formed as an integral part of the sensor (e.g.,both functionally and structurally).

The terms “interferants” and “interfering species” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and they are not to be limited toa special or customized meaning), and refer without limitation toeffects and/or species that interfere with the measurement of an analyteof interest in a sensor to produce a signal that does not accuratelyrepresent the analyte measurement. In one example of an electrochemicalsensor, interfering species are compounds with an oxidation/reductionpotential that overlaps with the analyte to be measured, producing afalse positive signal. In another example of an electrochemical sensor,interfering species are substantially non-constant compounds (e.g., theconcentration of an interfering species fluctuates over time).Interfering species include but are not limited to compounds withelectroactive acidic, amine or sulfhydryl groups, urea, lactic acid,phosphates, citrates, peroxides, amino acids, amino acid precursors orbreak-down products, nitric oxide (NO), NO-donors, NO-precursors,acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine,dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate,tetracycline, tolazamide, tolbutamide, triglycerides, and uric acidelectroactive species produced during cell metabolism and/or woundhealing, electroactive species that arise during body pH changes and thelike.

The term “in vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a portion of a device (forexample, a sensor) adapted for insertion into and/or existence within aliving body of a host.

The term “medical device” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to an instrument, apparatus,implement, machine, contrivance, implant, in vitro reagent, or othersimilar or related article, including a component part, or accessorywhich is intended for use in the diagnosis of disease or otherconditions, or in the cure, mitigation, treatment, or prevention ofdisease, in man or other animals, or intended to affect the structure orany function of the body of man or other animals. Medical devices thatcan be used in conjunction with various embodiments of the analytesensor system include any monitoring device requiring placement in ahuman vessel, duct or body cavity, a dialysis machine, a heart-lungbypass machine, blood collection equipment, a blood pressure monitor, anautomated blood chemistry analysis device and the like.

The terms “membrane” and “membrane system” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to apermeable or semi-permeable membrane that can be comprised of one ormore domains and is typically constructed of materials of one or moremicrons in thickness, which is permeable to oxygen and to an analyte,e.g. glucose or another analyte. In one example, the membrane systemincludes an immobilized glucose oxidase enzyme, which enables a reactionto occur between glucose and oxygen whereby a concentration of glucosecan be measured.

The term “membrane break-in” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to equilibration of the membraneto its surrounding environment (e.g., physiological environment invivo).

The term “needle” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a slender hollow instrument for introducingmaterial into or removing material from the body.

The term “non-constant noise” or non-constant background” as used hereinare broad terms, and are to be given their ordinary and customarymeaning to a person of ordinary skill in the art (and it is not to belimited to a special or customized meaning), and refer withoutlimitation to a component of the background signal that is relativelynon-constant, for example, transient and/or intermittent. For example,certain electroactive compounds, are relatively non-constant (e.g.,intermittent interferents due to the host's ingestion, metabolism, woundhealing, and other mechanical, chemical and/or biochemical factors),which create intermittent (e.g., non-constant) “noise” on the sensorsignal that can be difficult to “calibrate out” using a standardcalibration equations (e.g., because the background of the signal doesnot remain constant).

The term “non-enzymatic” as used herein is a broad term, and is to begiven their ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a lack of enzyme activity. Insome embodiments, a “non-enzymatic” membrane portion contains no enzyme;while in other embodiments, the “non-enzymatic” membrane portioncontains inactive enzyme. In some embodiments, an enzyme solutioncontaining inactive enzyme or no enzyme is applied.

The terms “operatively connected,” “operatively linked,” “operablyconnected,” and “operably linked” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to one or morecomponents linked to one or more other components. The terms can referto a mechanical connection, an electrical connection, or any connectionthat allows transmission of signals between the components. For example,one or more electrodes can be used to detect the amount of analyte in asample and to convert that information into a signal; the signal canthen be transmitted to a circuit. In such an example, the electrode is“operably linked” to the electronic circuitry. The terms include wiredand wireless connections.

The term “potentiostat” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to an electronic instrument thatcontrols the electrical potential between the working and referenceelectrodes at one or more preset values. Typically, a potentiostat worksto keep the potential constant by noticing changes in the resistance ofthe system and compensating inversely with a change in the current. As aresult, a change to a higher resistance would cause the current todecrease to keep the voltage constant in the system. In someembodiments, a potentiostat forces whatever current is necessary to flowbetween the working and counter electrodes to keep the desiredpotential, as long as the needed cell voltage and current do not exceedthe compliance limits of the potentiostat.

The term “pressure transducer” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to a component of anintra-arterial blood pressure monitor that measures the host's bloodpressure.

The terms “processor module” and “microprocessor” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to acomputer system, state machine, processor, and the like designed toperform arithmetic or logic operations using logic circuitry thatresponds to and processes the basic instructions that drive a computer.

The term “proximal to” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the spatial relationshipbetween various elements in comparison to a particular point ofreference. In general, the term indicates an element is locatedrelatively near to the reference point than another element.

The term “pump” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefers without limitation to a device used to move liquids, or slurries.In general, a pump moves liquids from lower pressure to higher pressure,and overcomes this difference in pressure by adding energy to the system(such as a water system).

The term “sensor break-in” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the time (after implantation)during which the sensor's signal is becoming substantiallyrepresentative of the analyte (e.g., glucose) concentration (e.g., wherethe current output from the sensor is stable relative to the glucoselevel). The signal may not be ‘flat’ when the sensor has broken-in, butin general, variation in the signal level at that point is due to achange in the analyte (e.g., glucose) concentration. In someembodiments, sensor break-in occurs prior to obtaining a meaningfulcalibration of the sensor output. In some embodiments, sensor break-ingenerally includes both electrochemical break-in and membrane break-in.

The terms “small diameter sensor,” “small structured sensor,” and“micro-sensor” as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefer without limitation to sensing mechanisms that are less than about2 mm in at least one dimension, and more preferably less than about 1 mmin at least one dimension. In some embodiments, the sensing mechanism(sensor) is less than about 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6,0.5, 0.4, 0.3, 0.2, or 0.1 mm. In some embodiments, the sensingmechanism is a needle-type sensor, wherein the diameter is less thanabout 1 mm (see, for example, U.S. Pat. No. 6,613,379 and U.S. PatentPublication No. US-2006-0020187-A1, each of which is incorporated hereinby reference in its entirety). In some alternative embodiments, thesensing mechanism includes electrodes deposited on a planar substrate,wherein the thickness of the implantable portion is less than about 1mm, see, for example U.S. Pat. No. 6,175,752 and U.S. Pat. No.5,779,665, both of which are incorporated herein by reference in theirentirety.

The terms “raw data,” “raw data stream”, “raw data signal”, “datasignal”, and “data stream” as used herein are broad terms, and are to begiven their ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refer without limitation to an analog or digital signalfrom the analyte sensor directly related to the measured analyte. Forexample, the raw data stream is digital data in “counts” converted by anA/D converter from an analog signal (for example, voltage or amps)representative of an analyte concentration. The terms can include aplurality of time spaced data points from a substantially continuousanalyte sensor, each of which includes individual measurements taken attime intervals ranging from fractions of a second up to, for example, 1,2, or 5 minutes or longer. In some embodiments, the terms can refer todata that has been integrated or averaged over a time period (e.g., 5minutes).

The term “regulator” or “flow control device,” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to a devicethat regulates the flow of a fluid or gas, for example, a valve or apump.

The term “retrograde” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and are not to be limited to a special or customized meaning), andrefers without limitation to orientation (e.g., of a catheter) againstthe direction of blood flow.

The term “sensing region” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the region of a monitoringdevice responsible for the detection of a particular analyte.

The terms “sensitivity” and “slope” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to an amount ofelectrical current produced by a predetermined amount (unit) of themeasured analyte. For example, in one preferred embodiment, a glucosesensor has a sensitivity (or slope) of from about 1 to about 25 picoAmpsof current for every 1 mg/dL of glucose.

The terms “sensor” and “sensor system” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to a device,component, or region of a device by which an analyte can be quantified.

The term “sheath” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefers without limitation to a covering or supporting structure thatfits closely around something, for example, in the way that a sheathcovers a blade. In one exemplary embodiment, a sheath is a slender,flexible, polymer tube that covers and supports a wire-type sensor priorto and during insertion of the sensor into a catheter.

The term “single point glucose monitor” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a device that canbe used to measure a glucose concentration within a host at a singlepoint in time, for example, some embodiments utilize a small volume invitro glucose monitor that includes an enzyme membrane such as describedwith reference to U.S. Pat. No. 4,994,167 and U.S. Pat. No. 4,757,022.It should be understood that single point glucose monitors can measuremultiple samples (for example, blood, or interstitial fluid); howeveronly one sample is measured at a time and typically requires some userinitiation and/or interaction.

The term “slot” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefers without limitation to a relatively narrow opening.

The terms “solvent” and “solvent system” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to substances (e.g.,liquids) capable of dissolving or dispersing one or more othersubstances. Solvents and solvent systems can include compounds and/orsolutions that include components in addition to the solvent itself.

The term “specific gravity” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the ratio of density of amaterial (e.g., a liquid or a solid) to the density of distilled water.

The term “spin coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a coating process in which athin film is created by dropping a raw material solution onto asubstrate while it is rotating.

The term “spray coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to coating, which involvesspraying a liquid coating substance onto an object or material.

The terms “substantial” and “substantially” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to asufficient amount that provides a desired function. For example, anamount greater than 50 percent, an amount greater than 60 percent, anamount greater than 70 percent, an amount greater than 80 percent, or anamount greater than 90 percent.

The term “twisted” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to united by having one part or end turnedin the opposite direction to the other, such as, but not limited to thetwisted strands of fiber in a string, yarn, or cable.

The term “valve” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefers without limitation to a device that regulates the flow ofsubstances (either gases, fluidized solids, slurries, or liquids), forexample, by opening, closing, or partially obstructing a passagewaythrough which the substance flows. In general, a valve allows no flow,free flow and/or gravity flow and/or metered flow through movement ofthe valve between one or more discreet positions.

The term “vascular access device” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to any device that is incommunication with the vascular system of a host. Vascular accessdevices include but are not limited to catheters, shunts, bloodwithdrawal devices, connectors, valves, tubing and the like.

Overview

Intensive care medicine or critical care medicine is concerned withproviding greater than ordinary medical care and/or observation topeople in a critical or unstable condition. In recent years, anincreasingly urgent need has arisen, for more intensive care medicine.People requiring intensive care include those recovering after majorsurgery, with severe head trauma, life-threatening acute illness,respiratory insufficiency, coma, hemodynamic insufficiency, severe fluidimbalance or with the failure of one or more of the major organ systems(life-critical systems or others). More than five million people areadmitted annually to intensive care units (ICUs) and critical care units(CCUs) in the United States.

Intensive care is generally the most expensive, high technology andresource intensive area of medical care. In the United States estimatesof the year 2000 expenditure for critical care medicine ranged from$15-55 billion accounting for about 0.5% of GDP and about 13% ofnational health care expenditure. As the U.S. population ages, thesecosts will increase substantially. Accordingly, there is an urgent needto reduce costs while at the same time reducing ICU/CCU mortality ratesby improving care.

Intensive medical care requires frequent testing and/or monitoring of avariety of analytes, such as but not limited to albumin, alkalinephosphatase, alanine transaminase, aspartate aminotransferase,bilirubin, blood urea nitrogen, calcium, CO₂, chloride, creatinine,glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactatedehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium,total protein, uric acid, a metabolic marker and a drug. Someembodiments disclosed herein are suitable for use in an intensive careor critical care unit of a medical care facility for substantiallycontinuously measuring the concentration of one or more analytes in thehost.

For example, diabetes is one medical condition requiring frequenttesting of the host's analyte levels (e.g., blood glucose levels), inhospital settings. Hosts having diabetes, for example, are at risk ofdeveloping hyperglycemia, a medical condition in which an excessiveamount of glucose circulates in a host. Perioperative hyperglycemia isassociated with increased rates and severity of myocardial infarction(MI) and stroke, while tight glucose control with intravenous (IV)insulin therapy is linked to a 30% reduction in mortality one year afteradmission for acute MI. Furthermore, strict in-hospital glucose controlis associated with 40% reductions of morbidity, mortality, sepsis,dialysis, blood transfusions, as well as reduced length of stay, reducedcosts and the like. On the other hand, diabetic hosts are alsosusceptible to hypoglycemia (e.g., excessively low circulating bloodglucose), which can cause shock and death (immediate problems), whichthe clinical staff rigorously avoids, often by maintaining the host atelevated blood glucose concentrations (which can degrade the clinicaloutcome in the long run) and causes the problems of hyperglycemiadiscussed above. Unfortunately, using generally available technology,tight glucose control requires frequent monitoring of the host by theclinical staff, IV insulin or injections, and on-time feeding. Frequentmonitoring typically requires a nurse or other staff member to measurethe host's glucose concentration using a lancet (to obtain a bloodsample) and a hand held glucose monitor. The nurse can perform this taskmany times a day (e.g., every hour or more frequently). This taskbecomes an undue burden that takes the nurse away from his/her otherduties, or requires extra staff. In spite of clinically demonstratedimprovements associated with tight glucose control, institutions areslow to adopt the therapy due to the increased workload on the staff aswell as a pervasive fear of hypoglycemia, which is potentially lifeending.

Therefore, there is an urgent need for devices and methods that offercontinuous, robust analyte monitoring, to improve patient care and lowermedical costs. Some embodiments disclose systems and methods to reduceand/or minimize the interaction required to regularly (e.g.,continuously) measure the host's glucose concentration. Additionaland/or alternative analytes can also be continuously monitored using thedevices and methods of the preferred embodiments. The preferredembodiments describe systems and methods for providing continuousanalyte monitoring while providing alarms or alerts that aid in avoidingadverse events.

The in vivo continuous analyte monitoring system of the preferredembodiments can be used in clinical settings, such as in the hospital,the doctor's office, long-term nursing facilities, or even in the home.The present device can be used in any setting in which frequent orcontinuous analyte monitoring is desirable. For example, in the ICU,hosts are often recovering from serious illness, disease, or surgery,and control of host glucose levels is important for host recovery. Forexample, use of a continuous glucose sensor as described in the someembodiments allows tight control of host glucose concentration andimproved host care, while reducing hypoglycemic episodes and reducingthe ICU staff work load. For example, the system can be used for theentire hospital stay or for only a part of the hospital stay.

In another example, the continuous glucose monitor of the preferredembodiments can be used in medical settings wherein the host is unableto communicate with the medical staff, such as an ER setting. Forexample, in the ER, a host may be unconscious and therefore unable tocommunicate with the staff. In another example, a very young, non-verbalhost may also be unable to communicate with the staff regarding his orher condition. In still another example, a host undergoing surgery isunable to communicate with the anesthesiologist, due to certain drugsbeing delivered. Routine use of a continuous analyte monitors (e.g.,glucose, calcium, sodium, potassium, CO₂, chloride, blood urea nitrogen,creatinine, pH, oxygen, albumin, total protein, alkaline phosphatase,alanine amino transferase, aspartate amino transferase, bilirubin,phosphate, electrolytes, hematocrit and/or drugs) can enable medicalstaff to monitor and respond to analyte concentration changes indicativeof the host's condition without host input.

In yet another example, a continuous analyte monitor can be used in thegeneral hospital population to monitor host analyte concentrations, forvarious lengths of time, such as during the entire hospital stay or fora portion of the hospital stay (e.g., only during surgery). For example,a diabetic host's glucose concentration can be monitored during his orher entire stay. In another example, a cardiac host's glucose can bemonitored during surgery and while in the ICU, but not after being movedto the general host population. In another example, a jaundiced newborninfant can have his or her bilirubin concentration continuouslymonitored by an in-dwelling continuous analyte monitor until thecondition has receded.

In addition to use in the circulatory system, the analyte sensor of thepreferred embodiments can be used in other body locations. In someembodiments, the sensor is used subcutaneously. In another embodiment,the sensor can be used intracranially. In another embodiment, the sensorcan be used within the spinal compartment, such as but not limited tothe epidural space. In some embodiments, the sensor of the preferredembodiments can be used with or without a catheter.

Applications/Uses

One aspect of the preferred embodiments provides a system for in vivocontinuous analyte monitoring (e.g., albumin, alkaline phosphatase,alanine transaminase, aspartate aminotransferase, bilirubin, blood ureanitrogen, calcium, CO₂, chloride, creatinine, glucose, gamma-glutamyltranspeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium,oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, ametabolic marker, a drug, various minerals, various metabolites, and thelike) that can be operatively coupled to a catheter to measure analyteconcentration within the host's blood stream. In some embodiments, thesystem includes an analyte sensor that extends a short distance into theblood stream (e.g., out of the catheter) without substantially occludingthe catheter or the host's blood stream. The catheter can be fluidlycoupled to additional IV and diagnostic devices, such as a saline bag,an automated blood pressure monitor, or a blood chemistry monitordevice. In some embodiments, blood samples can be removed from the hostvia the sensor system, as described elsewhere herein. In one embodiment,the sensor is a glucose sensor, and the medical staff monitors thehost's glucose level. In other embodiments, described elsewhere herein,the analyte sensor is disposed within or on the catheter itself, such asthe in vivo portion of the catheter. In still other embodiments, theanalyte sensor is disposed entirely within and/or on the fluid coupler,which is in turn fluidly coupled to a catheter or other vascular accessdevice, as described elsewhere herein.

FIGS. 1A to 1J illustrate two embodiments of an exemplary analyte sensorsystem 10 for measuring an analyte, as described elsewhere herein, thatincludes a catheter 12 configured to be inserted or pre-inserted into ahost's blood stream. In clinical settings, catheters are often insertedinto hosts to allow direct access to the circulatory system withoutfrequent needle insertion (e.g., venipuncture). Suitable catheters canbe sized as is known and appreciated by one skilled in the art, such asbut not limited to from about 1 French (0.33 mm) or less to about 30French (10 mm) or more; and can be, for example, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 French (3 French isequivalent to about 1 mm) and/or from about 33 gauge or less to about 16gauge or more, for example, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23,22, 21, 20, 19, 18, 17, or 16 gauge. Additionally, the catheter can beshorter or longer, for example 0.75, 1.0, 1.25, 1.5, 1.75, 2.0 inches inlength or longer. In some embodiments, the catheter is a venouscatheter. In other embodiments, the catheter is configured for insertioninto a peripheral or a central artery. In some embodiments, the catheteris configured to extend from a peripheral artery to a central portion ofthe host's circulatory system, such as but not limited to the heart. Instill other embodiments, the catheter is configured for insertion intoneonatal or other pediatric hosts (e.g., 22-24 gauge or smaller). Thecatheter can be manufactured of any medical grade material known in theart, such as but not limited to polymers and glass as described herein.A catheter can include a single lumen or multiple lumens. A catheter caninclude one or more perforations, to allow the passage of host fluidthrough the lumen of the catheter.

The terms “inserted” or “pre-inserted” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to insertion of onething into another thing. For example, a catheter can be inserted into ahost's blood stream. In some embodiments, a catheter is “pre-inserted,”meaning inserted before another action is taken (e.g., insertion of acatheter into a host's blood stream prior to insertion of a sensor intothe catheter). In some exemplary embodiments, a sensor is coupled to apre-inserted catheter, namely, one that has been previously inserted (orpre-inserted) into the host's circulatory system. Alternatively, thesensor and the catheter can be configured to be inserted together and/orthe sensor can be integrally formed with the catheter.

Referring now to FIGS. 1A to 1J, in some embodiments, the catheter 12 isa thin, flexible tube having a lumen 12 a, such as is known in the art.In some embodiments, the catheter can be rigid; in other embodiments,the catheter can be custom manufactured to desired specifications (e.g.,rigidity, dimensions, etc). The catheter can be a single-lumen catheteror a multi-lumen catheter. In some embodiments, the catheter is aperipheral catheter configured and arranged for insertion into aperipheral vessel (e.g., vein and/or artery) in a host's arm and/or leg.In some embodiments, the catheter is a central catheter, configured andarranged for insertion into a host's central vessel (e.g., internaljugular vein, subclavian vein, femoral vein and/or pulmonary artery). Atthe catheter's proximal end is a small orifice 12 b for fluid connectionof the catheter to the blood stream. At the catheter's distal end is aconnector 18, such as a Leur connector or other fluid connector known inthe art.

The illustrations of FIGS. 1A to 1J show two exemplary embodiments ofthe connector 18 including a flange 18 a and a duct 18 b. In theexemplary embodiment, the flange 18 a is configured to enable connectionof the catheter to other medical equipment (e.g., saline bag, pressuretransducer, blood chemistry device, and the like) or capping (e.g., witha bung and the like). Although one exemplary connector is shown, oneskilled in the art appreciates a variety of standard or custom madeconnectors suitable for use with the preferred embodiments. The duct 18b is in fluid communication with the catheter lumen and terminates in aconnector orifice 18 c.

In some embodiments, the catheter is inserted into the host's bloodstream, such as into a vein or artery by any useful method known in theart. Generally, prior to and during insertion, the catheter is supportedby a hollow needle or trochar (not shown). For example, the supportedcatheter can be inserted into a peripheral vein or artery, such as inthe host's arm, leg, hand, or foot. Typically, the supporting needle isremoved (e.g., pulled out of the connector) and the catheter isconnected (e.g., via the connector 18) to IV tubing and a saline drip,for example. However, in one embodiment, the catheter is configured tooperatively couple to medical equipment, such as but not limited to asensor system of the preferred embodiments. Additionally and/oralternatively, the catheter can be configured to operatively couple toanother medical device, such as a pressure transducer, for measurementof the host's blood pressure.

In some embodiments, the catheter and the analyte sensor are configuredto indwell within the host's blood stream in vivo. An indwelling medicaldevice, such as a catheter or implant, is disposed within a portion ofthe body for a period of time, from a few minutes or hours to a fewdays, months, or even years. An indwelling catheter is typicallyinserted within a host's vein or artery for a period of time, often 2 ormore days, a month, or even a few months. In some embodiments, thecatheter can indwell in a host's artery or vein for the length of aperioperative period (e.g., the entire hospital stay) or for shorter orlonger periods. In some embodiments, the use of an indwelling catheterpermits continuous access of an analyte sensor to a blood stream whilesimultaneously allowing continuous access to the host's blood stream forother purposes, for example, the administration of therapeutics (e.g.,fluids, drugs, etc.), measurement of physiologic properties (e.g., bloodpressure), fluid removal, and the like.

Referring again to FIGS. 1A to 1J, the system 10 also includes ananalyte sensor 14 configured to extend through the catheter lumen 12 a(see FIG. 1E), out of the catheter orifice 12 b and into the host'sblood stream by about 0.010 inches to about 1 inch, or shorter or longerlengths. In some embodiments, however, the sensor may not extend out ofthe catheter, for example, can reside just inside the catheter tip. Thesensor can extend through the catheter in any functional manner. In someembodiments, the sensor is configured to be held (e.g., located,disposed) on an inner surface (e.g., the lumenal surface) or outersurface of the catheter. In some embodiments, the sensor is deposited(e.g., formed) on a surface of the catheter. In some embodiments, asensor is attached to a surface of the catheter, such as by an adhesiveand/or welding. In some other embodiments, the sensor is configured to“free float” within the lumen of the catheter. In some embodiments, thesensor resides within the fluid coupler.

In some embodiments, the sensor 14 is configured to measure theconcentration of an analyte (e.g., albumin, alkaline phosphatase,alanine transaminase, aspartate aminotransferase, bilirubin, blood ureanitrogen, calcium, CO₂, chloride, creatinine, glucose, gamma-glutamyltranspeptidase, hematocrit, lactate, lactate dehydrogenase, magnesium,oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, ametabolic marker, various drugs, various minerals, various metabolites,and the like) within the host's blood stream. In some preferredembodiments, the sensor includes at least one electrode (see, e.g., FIG.3B), for example a working electrode; however any combination of workingelectrode(s), reference electrode(s), and/or counter electrode(s) can beimplemented as is appreciated by one skilled in the art. For example, insome preferred embodiments, the sensor includes at least two workingelectrodes, as is described with reference to FIGS. 3D through 3I. Instill other embodiments, two or more analyte sensors are in fluidcommunication with the vascular access device (e.g., disposed within thevascular access device), such that two or more analytes can be monitoredsimultaneously, and/or sequentially, continuously and/or intermittently,and the like. Preferably, the sensor 14 includes at least one exposedelectroactive area (e.g., working electrode), a membrane system (e.g.,including an enzyme), a reference electrode (proximal to or remote fromthe working electrode), and an insulator material. Various systems andmethods for design and manufacture of continuous analyte sensors aredescribed in more detail elsewhere herein. In some embodiments, thesensor is a needle-type continuous analyte sensor, configured asdisclosed in U.S. Patent Publication No. US-2006-0020192-A1 and U.S.Patent Publication No. US-2006-0036143-A1, both of which areincorporated herein by reference in their entirety. In some embodiments,the sensor is disposed on a planar substrate, configured as disclosed inU.S. Pat. No. 6,175,752, U.S. Pat. No. 6,512,939 and U.S. Pat. No.7,402,153, each of which are incorporated herein by reference in theirentirety. In some embodiments, the sensor is configured to measureglucose concentration. Exemplary sensor configurations are discussed inmore detail, elsewhere herein.

Referring to an embodiment illustrated in FIGS. 1A to 1E, the sensor hasa proximal end 14 a and a distal end 14 b. At its distal end 14 b, thesensor 14 is associated with (e.g., connected to, held by, extendsthrough, and the like) a fluid coupler 20 having first and second sides(20 a and 20 b, respectively). The fluid coupler is configured to mate(via its first side 20 a) to the catheter connector 18. In oneembodiment, a skirt 20 c is located at the fluid coupler's first sideand includes an interior surface 20 d with threads 20 e (see FIGS. 1Dand 1E). In this embodiment, the fluid coupler is configured to matewith the connector flange 18 a, which is screwed into the fluid couplervia the screw threads. However, in other embodiments, the fluid coupleris configured to mate with the connector using any known matingconfiguration, for example, a snap-fit, a press-fit, aninterference-fit, and the like, and can include a locking mechanism toprevent separation of the connector and fluid coupler. The fluid coupler20 includes a lumen 20 f extending from a first orifice 20 h on itsfirst side 20 a to a second orifice 20 i located on the fluid coupler'ssecond side 20 b (FIGS. 1C1 to 1E). When the catheter connector is matedwith the fluid coupler, the catheter's lumen 12 a is in fluidcommunication with the fluid coupler's lumen 20 f via orifices 18 c and20 h.

FIGS. 1A to 1D show one embodiment of a fluid coupler 20, namely, aY-coupler; however, any known coupler configuration can be used,including but not limited to a straight coupler, a T-coupler, across-coupler, a custom configured coupler, and the like. In someembodiments, the fluid coupler includes at least one valve (e.g., aseptum, a 3-way valve, a stop-cock valve), which can be used for avariety of purposes (e.g., injection of drugs). As another example,FIGS. 1F-1J illustrate a fluid coupler configured for connection of thesensor to sensor electronics via a female socket 20 n configured toreleasably mate with a male plug on an electronic cable. The fluidcoupler can be made of any convenient material, such as but not limitedto plastic, glass, metal or combinations thereof and can be configuredto withstand known sterilization techniques.

In the exemplary embodiment, the second side 20 b of the fluid coupler20 is configured to be operably connected to IV equipment, anothermedical device or to be capped, and can use any known matingconfiguration, for example, a snap-fit, a press-fit, aninterference-fit, and the like. In one exemplary embodiment, the secondside 20 b is configured to mate with a saline drip, for delivery ofsaline to the host. For example, the saline flows from an elevated bagof sterile saline via tubing, through the fluid coupler, through thecatheter and into the host's blood system (e.g., vein or artery). Inanother embodiment, a syringe can be mated to the fluid coupler, forexample, to withdraw blood from the host, via the catheter. Additionalconnection devices (e.g., a three-way valve) can be operably connectedto the fluid coupler, to support additional functionality and connectionof various devices, such as but not limited to a blood pressuretransducer.

Referring to the exemplary embodiment of FIGS. 1A and 1E, at least aportion of the sensor 14 passes through the fluid coupler 20 (e.g., thefluid coupler lumen 20 f) and is operatively connected to sensorelectronics (not shown) via a hardwire 24. In alternative embodimentshowever, the sensor electronics can be disposed in part or in whole withthe fluid coupler (e.g., integrally with or proximal to) or can bedisposed in part or in whole remotely from the fluid coupler (e.g., on astand or at the bed side). Connections between the sensor and sensorelectronics (in part or in whole) can be accomplished using known wiredor wireless technology. In one exemplary embodiment, the sensor ishardwired to the electronics located substantially wholly remote fromthe fluid coupler (e.g., disposed on a stand or near the bedside); oneadvantage of remote electronics includes enabling a smaller sized fluidcoupler design. In another exemplary embodiment, a portion of the sensorelectronics, such as a potentiostat, is disposed on the fluid couplerand the remaining electronics (e.g., electronics for receiving, dataprocessing, printing, connection to a nurses' station, etc.) aredisposed remotely from the fluid coupler (e.g., on a stand or near thebedside). One advantage of this design can include more reliableelectrical connection with the sensor in some circumstances. In thisembodiment, the potentiostat can be hardwired directly to the remainingelectronics or a transmitter can be disposed on or proximal to the fluidcoupler, for remotely connecting the potentiostat to the remainingelectronics (e.g., by radio frequency (RF)). In another exemplaryembodiment, all of the sensor electronics can be disposed on the fluidcoupler. In still another embodiment, the sensor electronics disposed onthe fluid coupler include a potentiostat.

Referring again to FIGS. 1A to 1E, a protective sheath 26 is configuredto cover at least a portion of the sensor 14 during insertion, andincludes hub 28 and slot 30. In general, the protective sheath protectsand supports the sensor prior to and during insertion into the catheter12 via the connector 18. The protective sheath can be made ofbiocompatible polymers known in the art, such as but not limited topolyethylene (PE), polyurethane (PE), polyvinyl chloride (PVC),polycarbonate (PC), nylon, polyamides, polyimide,polytetrafluoroethylene (PTFE), Teflon, nylon and the like. Theprotective sheath includes a hub 28, for grasping the sheath (e.g.,while maintaining sterilization of the sheath). In this embodiment, thehub additionally provides for mating with the second side 20 b of thefluid coupler 20, prior to and during sensor insertion into thecatheter. In this exemplary embodiment, the slot of the protectivesheath is configured to facilitate release of the sensor therefrom. Inthis embodiment, after the sensor has been inserted into the catheter,the hub is grasped and pulled from the second side of the fluid coupler.This action peels the protective sheath from the sensor (e.g., thesensor slides through the slot as the sheath is removed), leaving thesensor within the catheter. The second side of the fluid coupler can beconnected to other medical devices (e.g., a blood pressure monitor) oran IV drip (e.g., a saline drip), or capped. In alternative embodiments,the sheath can fold (e.g., fold back or concertinas) or retract (e.g.,telescope) during insertion, to expose the sensor. In other embodiments,the sheath can be configured to tear away from the sensor before,during, or after insertion of the sensor. In still other embodiments,the sheath can include an outlet hole 30 a, to allow protrusion of thesensor from the back end of the sheath (e.g., near the hub 28). Oneskilled in the art will recognize that additional configurations can beused, to separate the sensor 14 from the sheath 26.

In some embodiments, the sensor includes at least two working electrodes14, which can be twisted and/or bundled, such as in a helical and/orcoaxial configuration. In some embodiments, the two working electrodesare twisted into a “twisted pair,” which can be configured to beinserted into and to extend within a vascular access device, such as acatheter 12 or cannula implanted in a host's vein or artery, as isdescribed in more detail in the section entitled “Integrated SensorSystem.” In some embodiments, the twisted pair is configured to residewithin the lumen 12 a of the catheter 12; while in other embodiments,the twisted pair is configured to protrude from the catheter's proximalorifice 12 b. In still other embodiments, the twisted pair is configuredto intermittently protrude from the catheter's proximal orifice 12 b.

In some embodiments, the sheath 26 can be optional, depending upon thesensor design. For example, the sensor can be inserted into a catheteror other vascular access device with or without the use of a protectivesheath). In some embodiments, the sensor can be disposed on the outersurface of a catheter (as described elsewhere herein) or on the innersurface of a catheter; and no sheath is provided. In other embodiments,a multi-lumen catheter can be provided with a sensor already disposedwithin one of the lumens; wherein the catheter is inserted into thehost's vein or artery with the sensor already disposed in one of thelumens. In one exemplary embodiment, the system includes a catheterhaving multiple lumens, and is configured and arranged to infuse a fluidin a first lumen of the catheter and to draw back a biological sampleinto a second lumen of the catheter. In a further embodiment, an analytesensor is located in the second lumen of the catheter. In someembodiments, the system is configured to infuse a fluid into the secondlumen, such as to reinfuse a drawn back sample into the host and/or towash the sensor. In some embodiments, a flow control device isconfigured and arranged for infusion of at least two solutions, such asvia a multi-lumen catheter, and includes at least two valves, such asdescribed with reference to FIGS. 8A through 10D.

In some alternative embodiments, an analyte sensor is integrally formedon a catheter. In various embodiments, the catheter can be placed into ahost's vein or artery in the usual way a catheter is inserted, as isknown by one skilled in the art, and the host's analyte concentrationmeasured substantially continuously. In some embodiments, the sensorsystem can be coupled to one or more additional devices, such as asaline bag, an automated blood pressure monitor, a blood chemistrymonitor device, and the like. In one exemplary embodiment, theintegrally formed analyte sensor is a glucose sensor.

FIGS. 1F through 1J illustrate another embodiment of the sensor system,wherein the fluid coupler 20 includes a housing 20 j configured andarranged for electrical connection of the analyte sensor 14 to at leastsome system electronics, such as an electronic cable (not shown). Thehousing 20 j includes a housing cover 20 k and an electrical connector20 n. While a female socket 20 n (e.g., configured to releasably matewith a male plug) is shown, any electrical connection known in the artcan be used, as is appreciate by one skilled in the art.

FIGS. 1G-1H are exploded and cut-away views, respectively, of theembodiment shown in FIG. 1F. The encircled portion of FIG. 1H is shownin FIG. 1J and illustrates the configuration of the distal portion ofthe analyte sensor 14 within the housing 20 j, in this embodiment. Theanalyte sensor can be configured and arranged to detect one or moreanalytes, as described elsewhere herein. The proximal portion (ex vivoportion) of the analyte sensor 14 is configured and arranged forelectrical connection with the sensor electronics via one or moreelastomeric contacts and/or connectors 20 s and a printed circuit board(PCB) 20 t disposed within the housing. In this embodiment, theconnection is a solderless connection. However, in some embodiments,electrical connection of the electrodes to the electronics can be madeby other means, for example, wires, contact pads, pogo pins, domedmetallic contacts, cantilevered fingers, metallic springs, solderingand/or conductive adhesive. In the embodiment shown in FIGS. 1G-1J, anelastomeric contact and/or connector 20 s, which can be manufactured ofan conductive elastomeric material such as a carbon black elastomer,makes an electrical connection between each of the sensor's electrodes(e.g., working (plus or minus enzyme), counter and/or referenceelectrodes) and the PCB. For example, as shown in FIG. 1J, theelectrodes make contact with the elastomeric contacts, and theelastomeric contacts make contact with the PCB. The PCB is configuredand arranged to make an electrical connection with at least some of thesystem electronics, such as but not limited to by socket 20 n.Conductive elastomers are advantageously employed because theirresilient properties create a natural compression against mutuallyengaging contacts, forming a secure press fit therewith. In someembodiments, conductive elastomers can be molded in such a way thatpressing the elastomer against an adjacent contact performs a wipingaction on the surface of the contact, thereby creating a cleaning actionduring initial connection. Additionally, in some embodiments, the sensor14 extends through the contacts 20 s wherein the sensor is electricallyand mechanically secured by the relaxation of elastomer around thesensor.

In an alternative embodiment, a conductive, stiff plastic forms thecontacts, which are shaped to comply upon application of pressure (forexample, a leaf-spring shape). Contacts of such a configuration can beused instead of a metallic spring, for example, and advantageously avoidthe need for crimping or soldering through compliant materials;additionally, a wiping action can be incorporated into the design toremove contaminants from the surfaces during connection. Non-metalliccontacts can be advantageous because of their seamlessmanufacturability, robustness to thermal compression, non-corrosivesurfaces, and native resistance to electrostatic discharge (ESD) damagedue to their higher-than-metal resistance.

While in this embodiment (e.g., shown in FIGS. 1H and 1J), the proximalportion (e.g., part of the ex vivo portion, also referred to herein asthe first portion) of each electrode physically contacts the bottom of(e.g., beneath) an elastomeric connector, the electrodes can make anelectrical connection with elastomeric contacts by a variety of otherways. For example, in some embodiments, one or more of the electrodescan contact the top and/or side of the elastomeric contacts (e.g., aboveand/or beside). In still other embodiments, an electrode can intersectan elastomeric contact (e.g., pass through at least a portion of theelastomeric contact). In yet another embodiment, the proximal portion ofan electrode can be wrapped around an elastomeric contact. Additionalconfigurations are considered in the preferred embodiments. For example,the different configurations can be combined, such as for example, withone electrode touching the bottom of a first elastomeric contact, asecond electrode touching the top of a second elastomeric contact, and athird electrode passing through yet another elastomer contact.

In some embodiments, the interior of the housing is configured to guideplacement of the electrodes for contact with the elastomeric contacts,which can simplify manufacturing and ensure formation of a goodelectrical contact between each electrode and its correspondingelastomeric contact. For example, in the embodiment shown in FIGS. 1Hand 1J, pathways (e.g., recessed) are provided, to guide the placementof the electrode wires within the housing, and wells or cups areprovided to receive the elastomeric contacts. For example, in FIG. 1G,the proximal portion of each of the sensor's electrodes are receivedinto one of the three pathways provided, an elastomeric contact 20 s isplaced in each of the three wells, and then the PCB 20 t is placed ontop of the elastomeric contacts. Then, the housing cover 20 k, which, insome embodiments, includes a connector 20 n, is applied to close thehousing.

FIG. 1K illustrates another embodiment of the analyte sensor 14 isincorporated into a fluid coupler 20. In this embodiment, the sensor isconfigured such that it extends at least a portion of the length of thelumen 20 f of the fluid coupler, but does not extend out of the fluidcoupler itself (e.g., past the fluid coupler's first orifice 20 h). Whenthe fluid coupler of this embodiment is fluidly coupled to an implantedcatheter, the first side 20 a of the fluid coupler releasably mates withthe catheter hub 18, such that a portion of the fluid coupler's firstorifice 20 h is located within a portion of the catheter hub's duct orlumen (e.g., 18 b, see FIGS. 1D-1E). Accordingly, in this embodiment,the sensor tip 14 a can be located within the catheter hub's duct orlumen. Advantageously, this embodiment simplifies device installation asno insertion of the sensor into a catheter is required. Additionally,sensor performance is maintained because the sensor is protected by thefluid coupler's hard structure during connection of the fluid coupler tothe catheter (e.g., the sensor cannot be accidentally touched, bent orflexed during installation).

As described elsewhere herein, function of an enzymatic analyte sensoris dependent upon the kinetics of the enzyme comprised in the sensor.For example, the function of a glucose sensor is dependent upon thekinetics of the glucose oxidase contained in the sensor's membrane. Asis understood by one skilled in the art, enzyme kinetics are influencedby the availability of the reactants. When all required reactants arefreely available, the enzyme will react at its maximum rate, given theprevailing temperature and pH conditions. If, on the other hand, theconcentration of one of the reactants is low (e.g., limiting), theenzyme reaction will proceed at a slower rate, which is associated withthe concentration of the limited reactant. Accordingly, to measure theconcentration of a particular reactant (e.g., the analyte), thatreactant should be present in limiting amounts. In other words, theother reactants (e.g., a co-reactant) should be present in excess (e.g.,non-limiting amounts). For example, glucose and oxygen are the reactantsof some GOX-containing glucose sensors. Since the analyte is glucose,oxygen (e.g., the co-reactant) should be present in excess (e.g.,non-limiting), so that the reaction rate is dependent upon the glucoseconcentration. In some circumstances, however, the co-reactant islimiting. For example, if ischemia occurs around and/or near the sensor,the amount of available oxygen can be reduced and thus become thelimiting reactant. In another example, the analyte can exist in excess(e.g., in the body) relative to the concentration of a reactant, such asoxygen. In some embodiments, the sensor is configured to compensate fora limiting reactant, such as but not limited to oxygen. For example, themembrane can be configured and arranged to restrict the amount of excessreactant that diffuses therethrough (e.g., see the section entitled“Resistance Domain.”) In other embodiments, the sensor can be configuredto increase the level of limiting reactant (e.g., co-reactant). Forexample, in some embodiments, the membrane can include a domainconfigured to increase the concentration of oxygen. In otherembodiments, the vascular access device, such as the ex vivo portion ofa catheter or a fluid coupler can be configured to increase the amountof oxygen (e.g., co-reactant) available to the enzyme. For example, thefluid coupler 20 of FIG. 1K includes an enrichment body 20 p configuredand arranged to increase the oxygen concentration at the sensor 14. Anenrichment body 20 p can be provided in many forms. For example, in theembodiment shown in FIG. 1K, the enrichment body includes an “oxygenport” including a membrane, plug or filter located in a side of thefluid coupler. In this embodiment, the oxygen port intersects the fluidcoupler wall, such that oxygen can diffuse from the exterior of thefluid coupler to the lumen 20 f. In some embodiments, the oxygen portincludes a plug and/or membrane formed of silicone, ePTFE or otherpolymer known to increase oxygen diffusion. In other embodiments, theenrichment body 20 p includes an “oxygen capacitor” configured to absorboxygen when the oxygen concentration (e.g., around the sensor) is high,and to release the absorbed (e.g., stored) oxygen when the oxygenconcentration is low. For example, in some embodiments, the infusionsolution is oxygenated, such that as the infusion solution flows throughthe fluid coupler and/or catheter and contacts the oxygen capacitor, thecapacitor absorbs at least some of the oxygen present in the solution.Then, when blood is drawn back and contacts the capacitor, at least someof the oxygen stored in the capacitor diffuses into the blood. Forexample, in some embodiments, the oxygen capacitor is anoxygen-absorbing and oxygen-releasing polymer applied to the lumenalsurface of the fluid coupler and/or catheter. In other embodiments, theoxygen capacitor is a membrane or plug attached to the lumenal surfaceof the catheter and/or fluid coupler. In yet another embodiment, theenrichment body is inserted into the lumen of the fluid coupler and/orcatheter hub.

FIG. 1L illustrated an embodiment similar to that of FIG. 1K, exceptthat at least a portion of the sensor 14 extends toward the fluidcoupler's 20 second side 20 b. In some embodiments, the sensor tipextends to the fluid coupler's second orifice 20 i, but not there past.In other embodiments, the sensor is configured to extend into connectedtubing. Accordingly, in this embodiment, the sensor's electroactivesurface(s) can be located at any point along the length of the fluidcoupler's lumen 20 f.

FIG. 1M illustrates yet another embodiment of an analyte sensorincorporated into a fluid coupler 20. In this embodiment, at least oneanalyte sensor 14 is located on a support 20 q that is located on thelumenal surface of the fluid coupler. In some embodiments, the support,including the at least one analyte sensor located thereon, is insertedinto the fluid coupler via an orifice (e.g., 20 i). In otherembodiments, the fluid coupler includes a port (e.g., an orifice, holeor opening, not shown) configured and arranged to receive the support(e.g., the port and the support are configured to mate with each other),such as via insertion through the wall of the fluid coupler. In someembodiments, the at least one analyte sensor comprises two or moreanalyte sensors, wherein the analyte sensors are configured to detectone or more analytes. In some embodiments, the at least one analytesensor comprises 3, 4, 5, 6, 7, 8, 9, 10 or more analytes sensors. Insome embodiments, the at least one analyte sensor comprises a pluralityof micro-fabricated sensors, such as but not limited to a sensor array.The sensor(s) can be applied to and/or deposited on the support usingany method known in the art, such as but not limited to thin and/or thinfilm techniques, printing, plating, and the like. In some embodiments,an analyte sensor is configured to intersect the support, such asdescribed with reference to FIGS. 2M-2Q. In some embodiments, the sensor(e.g., working electrode) is substantially flush with the support,similar to the manner of some glucose test strips that have electrodesprinted on a planar support using thin and/or thick film techniques. Insome embodiments, the sensor (e.g., working electrode) is at leastpartially embedded in the support. For example, the working electrodematerial can be deposited in a groove or well located on the support. Inpreferred embodiments, the support is manufactured from a polymer.Preferably, the polymer is configured for malleability duringmanufacture but also provides sufficient strength to function as a sideof the fluid coupler. In other embodiments, the support is formed from ametal, a ceramic or glass. The support can have any shape, such as aplanar or non-planar shape. In some embodiments, the support has aplanar lumenal surface (e.g., the surface of the support that faces thelumen of the fluid coupler). However, in other embodiments, thesupport's lumenal surface is curved. In some embodiments, the support(e.g., with sensor(s) applied thereto) is received into a port. In someembodiments, the support makes a friction fit into the port. In otherembodiments, the support and port are configured for a snap fit of thesupport into the port. In some embodiments, the support can be securedinto the port with an adhesive, hooks, pins, and/or via welding. Inother embodiments, the support (including one or more analyte sensors)is inserted into the lumen of the fluid coupler. For example, in oneembodiment, the fluid coupler does not include a port; rather thesupport (e.g., including sensors) is inserted through one of the fluidcoupler's orifices, such that the support is located adjacent to and/oron the fluid coupler's lumenal surface. In a further embodiment, thesupport is configured to conform to the lumenal surface of the fluidcoupler. In some embodiments, the support is attached to the lumenalsurface of the fluid coupler, such as with adhesive or welding. In someembodiments, a catheter hub includes a port configured for receipt ofthe support. Advantageously, manufacturing the sensor(s) on a supportand then integrating them with the fluid coupler simplify manufacturingand reduce costs by enabling high through put, automated manufacturingmethods. Additionally, a wider array of sensors and custom-order sensorscan be easily manufactured (e.g., as “panels” of sensors that test apanel of analytes) and subsequently integrated into the fluid couplersand/or catheter hubs. For example, in one embodiment cassettes ofsensors are manufactured in an automated reel-to-reel process whereinsensor panels (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17,18, 19 or 20 or more sensors) are applied to a continuous roll ofpolymer material (e.g., the support), wherein the individual sensorcassettes are subsequently cut out of the roll, such as using a die. Ina second automated process, the completed sensor cassettes are installedinto the ports of separately manufactured fluid couplers. Sensorelectronics, such as a PCB and electronic connectors are applied in yetanother automated process. In some embodiments, 2, 3, 4, 5, or moredifferent types of sensor cassettes (e.g., each type of sensor cassetteincludes a different panel of analyte sensors) can be manufactured(e.g., simultaneously on separate manufacturing lines or on a singleline at different times) and then subsequently integrated intoseparately manufactured fluid couplers. In other embodiments, for fluidcouplers and/or catheters hubs having different configurations, eachconfiguration includes a port configured to receive a single size and/orshape of sensor cassette, wherein the size and/or shape of the cassetteis associated with a fluid coupler or catheter configuration. In someembodiments, each type of sensor cassette (e.g., analyte panel) includesa unique shape, such that it must be received by a port configured tomate with it, similar to an interlocking lock and key, such that certaincassettes are used with certain fluid couplers and/or catheters. In someembodiments, certain interlocking cassette and port configurations areassociated with a particular panel of analytes and/or a client. In yetanother embodiment, the sensor cassettes are configured to bereplaceable prior-to and/or during use. For example, in one embodiment,the fluid coupler is provided with two or more types of cassettes (e.g.,different panels), such that the user inserts a selected cassette intothe fluid coupler's port prior to use. In an alternative embodiment, thefluid coupler can be provided with two or more cassettes of the sametype, such that the cassette can be changed out during use. For example,if a sensor on a first cassette fails, the cassette can be replaced witha second cassette of the same type. Analyte sensors and manufacturingmethods suitable for use with these embodiments can be found in U.S.Pat. No. 5,108,819, U.S. Pat. No. 5,178,957, U.S. Pat. No. 5,879,828,U.S. Pat. No. 6,175,752, U.S. Pat. No. 6,284,478, U.S. Pat. No.6,329,161, U.S. Pat. No. 6,565,509, U.S. Pat. No. 6,990,366, U.S. Pat.No. 6,134,461, U.S. Pat. No. 7,003,336, U.S. Pat. No. 6,784,274, U.S.Pat. No. 6,103,033, and U.S. Pat. No. 5,899,855, each of which isincorporated herein by reference in its entirety.

FIGS. 2A to 2B illustrate one exemplary embodiment of an analyte sensorintegrally formed on a catheter. The system 210 is configured to measurean analyte and generally includes a catheter 212 configured forinsertion into a host's blood stream (e.g., via a vein or artery) and asensor at least partially integrally formed on the catheter's exteriorsurface 232. Preferably, the sensor 214 includes at least one exposedelectroactive area 240 (e.g., a working electrode), a membrane system(e.g., including an enzyme), a reference electrode (proximal to orremote from the working electrode), and an insulator.

In this embodiment, the catheter includes a lumen 212 a and an orifice212 b at its proximal end, for providing fluid connection from thecatheter's lumen to the host's blood stream (see FIG. 2A).

In some embodiments, the catheter is inserted into a vein, as describedelsewhere herein. In other embodiments, the catheter is inserted into anartery, as described elsewhere herein. The catheter can be any type ofvenous or arterial catheter commonly used in the art (e.g., peripheralcatheter, central catheter, Swan-Gantz catheter, etc.). The catheter canbe made of any useful medical grade material (e.g., polymers and/orglass) and can be of any size, such as but not limited to from about 1French (0.33 mm) or less to about 30 French (10 mm) or more; forexample, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,or 20 French (3 French is equivalent to about 1 mm). In someembodiments, the catheter is configured and arranged for insertion intoneonatal or other pediatric hosts (e.g., 22-24 gauge or smaller). Incertain embodiments, the catheter can be a single lumen catheter or amulti-lumen catheter. In some embodiments, the catheter can include oneor more perforations, to allow the passage of host fluid through thelumen of the catheter. In one embodiment, the catheter is a dual-lumencatheter wherein a first lumen is configured to receive an analytesensor and a second lumen is configured for fluid infusion. In preferredembodiments, the catheter is configured such that the orifice of thefirst lumen is sufficiently proximal to connector (of the catheter)relative to the orifice of the second lumen, that samples drawn backinto the first lumen (e.g., to be tested by the analyte sensor) aresubstantially undiluted by the infused fluid.

At its distal end 212 c, the catheter 212 includes (e.g., in fluidcommunication) a connector 218. The connector can be of any known type,such as a Leur lock, a T-connector, a Y-connector, a cross-connector ora custom configuration, for example. In some embodiments, the connectorincludes at least one valve. At a second side 218 e (e.g., back end),the connector 218 can be operatively connected to a saline system (e.g.,saline bag and tubing), other medical devices (e.g., automatic bloodchemistry machine, dialysis machine, a blood bag for collecting donatedblood, etc.), or capped.

In some embodiments, the system 210 includes sensor electronics (notshown) operatively connected to the analyte sensor, wherein the sensorelectronics are generally configured to measure and/or process thesensor data as described in more detail elsewhere herein. In someembodiments, the sensor electronics can be partially or wholly disposedwith (e.g., integral with, disposed on, or proximal to) the connector218 at the distal end of the catheter or partially or wholly remote fromthe catheter (e.g., on a stand or on the bedside). In one embodiment,the sensor electronics disposed with the connector include apotentiostat. In some embodiments, the sensor electronics are configuredto measure the host's analyte concentration substantially continuously.For example, the sensor can measure the analyte concentrationcontinuously or at time intervals ranging from fractions of a second upto, for example, 1, 2, or 5 minutes or longer.

FIGS. 2C to 2F illustrate additional embodiments of the sensor shown inFIGS. 2A to 2B. The catheter 212 is shown with an integral sensor 214having at least one electrode 240 formed on its exterior surface 232(e.g., FIG. 2F). In general, the sensor can be designed with 1, 2, 3, 4or more electrodes and can be connected by traces (or the like) toelectrical contacts 218 d (or the like) at the second end of theconnector 218 (e.g., FIGS. 2A to 2F). In some embodiments, the sensor ishard-wired to the sensor electronics; alternatively, any operableconnection can be used. Preferably, the sensor includes at least oneworking electrode and at least one reference or counter electrode. Insome embodiments, the reference electrode is located proximal to the atleast one working electrode (e.g., adjacent to or near to the workingelectrode). In some alternative embodiments, the reference electrode islocated remotely from the working electrode (e.g., away from the workingelectrode, such as but not limited to within the lumen of the catheter212 (or connector 218), on the exterior of the sensor system, in contactwith the patient (e.g., on the skin), or the like). In some embodiments,the reference electrode is located proximal to or within the fluidconnector, such as but not limited to, coiled about the catheteradjacent to the fluid connector or coiled within the fluid connector andin contact with fluid flowing through the fluid coupler, such as salineor blood. In some embodiments, the sensor can also include one or moreadditional working electrodes (e.g., for measuring baseline, formeasuring a second analyte, or for measuring a substantially non-analyterelated signal, and the like, such as described in more detail in U.S.Patent Publication No. US-2005-0143635-A1 and U.S. Patent PublicationNo. US-2007-0027385-A1, which are incorporated herein by reference intheir entirety. In some embodiments one or more counter electrodes canbe provided on a surface of the catheter or within or on the fluidconnector.

In some of the preferred embodiments, the catheter is designed toindwell within a host's blood flow (e.g., a peripheral vein or artery)and remain in the blood flow for a period of time (e.g., the catheter isnot immediately removed). In some embodiments, the indwelling cathetercan be inserted into the blood flow for example, for a few minutes ormore, or from about 1 to 24 hours, or from about 1 to 10 days, or evenlonger. For example, the catheter can indwell in the host's blood streamduring an entire perioperative period (e.g., from host admittance,through an operation, and to release from the hospital).

In some embodiments, the catheter is configured as an intravenouscatheter (e.g., configured to be inserted into a vein). The catheter canbe inserted into any commonly used vein, such as in a peripheral vein(e.g., one of the metacarpal veins of the arm); in some embodiments(e.g., such as described with reference to FIGS. 1A to 1E) the analytesensor inserted into a catheter. In alternative embodiments, the sensoris integrally formed on a catheter such as described in more detail withreference to FIGS. 2A to 2F, for example. Other veins, such as leg orfoot veins, hand veins, or even scalp or umbilical veins, can also beused.

In addition to sensing analyte levels via a sensor system as describedherein, the intravenous catheter can be used for delivery of fluidsand/or drugs to the host's circulatory system. The catheter can beconfigured to be coupled to other medical devices or functions, forexample, saline, blood products, total parenteral feeding or medicationscan be given to the host via the indwelling intravenous catheter. Insome embodiments, the catheter can be operatively connected to a pump,such as an infusion pump, to facilitate flow of the fluids into the hostand a desired rate. For example, an infusion pump can pump saline intothe host at a rate of 1 cc per minute, or at higher or lower rates. Therate of infusion can be changed (increased or decreased). For example,an infusion can be temporarily stopped, to permit injection of painmedication into the IV system, followed by increasing the infusion rate(e.g., for 5 minutes) to rapidly deliver the pain medication to thehost's circulatory system.

In some embodiments, the catheter is configured as an arterial catheter(e.g., configured to be inserted into an arterial line or as part of anarterial line). Typically, an arterial catheter is inserted in the wrist(radial artery), armpit (axillary artery), groin (femoral artery), orfoot (pedal artery). Generally, arterial catheters provide access to thehost's blood stream (arterial side) for removal of blood samples and/orapplication of test devices, such as but not limited to a pressuretransducer (for measuring blood pressure automatically), however,arterial catheters can also be used for delivery of fluids ormedications. In one embodiment, a catheter is inserted into an arterialline and the sensor inserted into the catheter (e.g., functionallycoupled) as described elsewhere herein. Saline filled non-compressibletubing is then coupled to the sensor, followed by a pressure transducer.An automatic flushing system (e.g., saline) is coupled to the tubing aswell as a pressure bag to provide the necessary pressure. Electronicsare generally operatively coupled to the pressure transducer forcalculating and displaying a variety of parameters including bloodpressure. Other medical devices can also be connected to the arterialcatheter, to measure various blood components, such as but not limitedto O₂, CO₂, PCO₂, PO₂, potassium, sodium, pH, lactate, urea, bilirubin,creatinine, hematocrit, various minerals, various metabolites, and thelike.

In another embodiment, a blood pressure measurement system is insertedinto the host and can be used as is known in the art. The analyte sensor(e.g., glucose sensor), such as the embodiment shown in FIGS. 1A-1E, isinserted into the pre-inserted (e.g., already in-dwelling) catheterusing the following general methodology. First, the pressure transduceris temporarily disabled by disconnecting from the pre-inserted catheter.A cap (optionally) covers the protective slotted sheath and can beremoved so as to enable the sensor to be grasped at the fluid coupler.The sheath, which is generally more rigid than the sensor but lessflexible than a needle, is then threaded through the pre-insertedcatheter so as to extend beyond the catheter into the blood stream(e.g., by about 0.001 inches to about 1 inches). The sheath is thenremoved by sliding the sensor through a small outlet hole and/or slot inthe sheath. Thus, the sensor remains within the pre-inserted catheterand the fluid coupler, which supports the distal portion of the sensor,is coupled to the catheter itself Saline filled non-compressible tubingis then coupled to the second side (e.g., back end) of the fluidcoupler. The sensor electronics (whether adjacent to the fluid coupleror otherwise wired to the fluid coupler) are then operatively connected(e.g., wired or wirelessly) to the sensor to initiate sensor function.

In some embodiments, a portion of the sensor system (e.g., sensor,catheter, or other component) can be configured to allow removal ofblood samples from the host's blood stream (e.g., artery or vein).Sample removal can be done using any systems and methods known in theart, for example, as is practiced for removing a blood sample from anarterial catheter (e.g., and arterial line). In one such exemplaryembodiment, any tubing or equipment coupled to the second side of thefluid coupler is disconnected. A syringe is then be coupled to thesecond side and blood removed via the catheter by pulling back on thesyringe plunger. In a further embodiment, saline can be flushed throughthe fluid coupler and catheter. In another embodiment, the fluid couplercan be configured with a side valve, to allow coupling of a syringe, forremoval of blood samples or delivery of fluids, such as medications,without disconnecting attached tubing of equipment, and the like. Instill another embodiment, a valve or diaphragm, for access to the systemby a syringe, can be coupled into the tubing at a short distance fromthe fluid coupler. In yet another embodiment, the sensor is integrallyformed on the arterial catheter, such as the embodiment shown in FIGS.2A-2B, and tubing can be disconnected from the connector, a syringeoperably associated with the connector, and blood removed with thesyringe. After blood collection, the syringe is removed and the tubingreconnected to the connector.

In still another embodiment, the analyte sensor can be functionallycoupled to an extracorporeal blood flow device. A variety of devicesexist for testing various blood properties and/or analytes at thebedside, such as but not limited to the blood gas and chemistry devicesmanufactured by Via Medical, Austin, Tex., USA. These devices generallywithdraw a blood sample from the host, test the blood sample, and thenreturn it to the host. Such a device can be connected in series to thearterial catheter, with the sensor in-between, and using systems andmethods known in the art. In one embodiment, a sensor, such as theembodiment shown in FIGS. 1A-1E, is functionally connected to anin-dwelling arterial catheter, as described herein, and theextracorporeal blood flow device is connected to the second side of thefluid coupler. In an alternative embodiment, the sensor is integrallyformed on the arterial catheter, such as the embodiment shown in FIGS.2A-2F, and the extracorporeal blood flow device is functionallyconnected to the connector 218. Other devices, such as but not limitedto dialysis machines, heart-lung bypass machines or blood collectionbags, or other vascular access devices, can be functionally coupled tothe analyte sensor.

The analyte sensor system of the preferred embodiments can be designedwith a variety of alternative configurations. In some embodiments, thesensor is connected to a fluid connection device. The fluid connectiondevice in these embodiments can be any standard fluid connection deviceknown in the art, such as a fluid coupler, or a fluid coupler custommanufactured to preferred specifications. On its first side, the fluidcoupler is configured to couple to an existing catheter or cannula (asdescribed with reference to FIGS. 1A-1E). The catheter (or cannula) istypically inserted into a vascular access device and/or into a hospitalhost during a hospital stay. For example, the catheter can be insertedinto an arterial line (e.g., for removing blood samples or for measuringblood pressure using a pressure transducer) or a venous line (e.g., forintravenous delivery of drugs and other fluids). In general practice,the catheter is inserted into the host's blood vessel, for example, andmaintained there for a period of time during the host's hospital stay,such as part of the stay or during the entire stay (e.g.,perioperatively). In one alternative embodiment, another vascular accessdevice (e.g., other than a catheter) can be used to receive the sensor.In yet another alternative embodiment, the sensor system of thepreferred embodiments can be inserted into a vascular access device(e.g., rather than the vascular system directly). Some examples ofvascular access devices include but are not limited to, catheters,shunts, automated blood withdrawal devices and the like.

In some embodiments, such as the embodiment illustrated in FIGS. 1A to1E, the system 10 is configured such that the sensor is inserted into avascular access device, such as but not limited to a catheter 12 (e.g.,a catheter that has been inserted into the host's blood stream prior tosensor insertion). In general, catheters are small, flexible tubes(e.g., soft catheter) but they can also be larger, rigid tubes.Catheters are inserted into a host's body cavity, vessel, or duct toprovide access for fluid removal or insertion, or for access to medicalequipment. Catheters can also be inserted into extracorporeal devices,such as but not limed to an arterio-venous shunt for the transfer ofblood from an artery to a vein. Some catheters are used to direct accessto the circulatory system (e.g., venous or arterial catheters, SwanGantz catheters) to allow removal of blood samples, the infusion offluids (e.g., saline, medications, blood or total parenteral feeding) oraccess by medical devices (e.g., stents, extracorporeal blood chemistryanalysis devices, invasive blood pressure monitors, etc.).

Preferably, the sensor is designed to include a protective cap, asillustrated in FIGS. 1A-1E. Namely, FIGS. 1A and 1B illustrates thecatheter (the catheter cap having been removed prior to insertion), wellknown to those skilled in the art, which can be inserted into the host'sblood vessel using standard methods. The sensor 14 is configured formeasurement of an analyte (e.g., glucose) in the host's body, and is influid connection within the catheter lumen, which is in fluid connectionwith the fluid coupler 20 of the sensor. The first side 20 a of thefluid coupler 20 of the sensor is designed to couple to the catheter,e.g., by screwing or snapping thereon, and can also couple (on itssecond side 20 b) with other medical devices. One advantage of the fluidcoupler is that it provides for a small amount of bleed back, to preventair bubbles in the host's blood stream.

The exemplary sensor system 10 of FIGS. 1A and 1B further includes aslotted protective sheath 26 that supports and protects the sensorduring sensor insertion, for example, the sheath increases the sensorvisibility (e.g., the sensor is so thin that it can be difficult forsome people to see without the protective sheath) and provides for easeof sliding the sensor into the catheter. The slotted protective sheathis configured to fit within the fluid coupler and houses the sensorduring insertion of the sensor into the catheter (e.g., an indwellingcatheter within the host's blood flow). Preferably, the protectivesheath is substantially more rigid than the sensor and at the same timesubstantially more flexible that a standard syringe needle, howeverother designs are possible. To facilitate removal of the protectivesheath, a slot 30 is provided with an optional outlet hole 30 a, whichis described in more detail with reference to FIG. 1C, and a hub 28. Bygrasping and pulling the hub, the user (e.g., health care professional)can withdraw the protective sheath after coupling the fluid coupler tothe catheter. Prior to insertion of the sensor, a cap is provided, tocover the protective sheath, for example, to keep the sheath and sensorsterile, and to prevent damage to the components during shipping and/orhandling.

In general, the sensor system is configured with a potentiostat and/orsensor electronics that are operatively coupled to the sensor. In someembodiments, a portion of the sensor electronics, such as thepotentiostat, can be disposed directly on the fluid coupler. However,some or all of the sensor electronics (including the potentiostat) canbe disposed remotely from the fluid coupler (e.g., on the bedside or ona stand) and can be functionally coupled (e.g., wired or wireless), asis generally known to those skilled in the art.

FIGS. 1C1 and 1C2 are cross-sectional views (not to scale) of the fluidcoupler, including a protective sheath 26, a sensor 14, and a cap 32(cap to be removed prior to insertion) in one embodiment. The protectivesheath 26 extends through the fluid coupler and houses the sensor, forsensor insertion into a catheter. The protective sheath includes anoptional outlet hole 30 a, through which the sensor extends and a slot30 along a length of the protective sheath that communicates with theoutlet hole and enables the protective sheath to be removed after thesensor has been inserted into the host's body. The protective sheathincludes a hub 28 for ease of handling.

In some embodiments, the glucose sensor is utilized in combination withanother medical device (e.g., a medical device or access port that isalready coupled to, applied to, or connected to the host) in a hospitalor similar clinical setting. For example, a catheter can be insertedinto the host's vein or artery, wherein the catheter can is connected toadditional medical equipment. In an alternative example, the catheter isplaced in the host to provide quick access to the host's circulatorysystem (in the event of a need arising) and is simply capped. In anotherexample, a dialysis machine can be connected to the host's circulatorysystem. In another example, a central line can be connected to the host,for insertion of medical equipment at the heart (e.g., the medicalequipment reaches the heart through the vascular system, from aperipheral location such as a leg or arm pit).

In practice of coupling to a catheter, before insertion of the sensor,the access port is opened. In one exemplary embodiment of a pre-insertedcatheter that is capped, the cap is removed and the sensor inserted intothe catheter. The back end of the sensor system can be capped orattached to additional medical equipment (e.g., saline drip, bloodpressure transducer, dialysis machine, blood chemistry analysis device,etc.). In another exemplary embodiment, medical equipment (e.g., salinedrip, blood pressure transducer, dialysis machine, blood chemistryanalysis device, etc.) is already connected to the catheter. The medicalequipment is disconnected from the catheter, the sensor inserted into(and coupled to) the catheter and then the medical equipment reconnected(e.g., coupled to the back end of the sensor system).

In some embodiments, the sensor is inserted directly into the host'scirculatory system without a catheter or other medical device. In onesuch exemplary embodiment, the sheath covering the sensor is relativelyrigid and supports the sensor during insertion. After the sensor hasbeen inserted into the host's vein or artery, the supportive sheath isremoved, leaving the exposed sensor in the host's vein or artery. In analternative example, the sensor is inserted into a vascular accessdevice (e.g., with or without a catheter) and the sheath removed, toleave the sensor in the host's vein or artery (e.g., through thevascular access device).

In various embodiments, in practice, prior to insertion, the cap 32 overthe protective sheath is removed as the health care professional holdsthe glucose sensor by the fluid coupler 20. The protective sheath 26,which is generally more rigid than the sensor but more flexible than aneedle, is then threaded through the catheter so as to extend beyond thecatheter into the blood flow (e.g., by about 0.010 inches to about 1inches). The protective sheath is then removed by sliding the sensorthrough the (optional) outlet hole 30 a and slotted portion 30 of thesheath (e.g., by withdrawing the protective sheath by pulling the hub28). Thus the sensor remains within the catheter; and the fluid coupler20, which holds the sensor 14, is coupled to the catheter itself (viaits connector 18). Other medical devices can be coupled to the secondside of the fluid coupler as desired. The sensor electronics (e.g.,adjacent to the fluid coupler or otherwise coupled to the fluid coupler)are then operatively connected (e.g., wired or wirelessly) to the sensorfor proper sensor function as is known in the art.

In another embodiment, the catheter 12 includes a plurality ofperforations (e.g., holes) that allow the host's fluid (e.g., blood) toflow through the lumen 12 a of the catheter. The fluid flowing throughthe catheter can make contact with a sensor 14 inserted therein. In afurther embodiment, the sensor does not protrude out of the catheter'stip 12 b and the host's blood flowing through the perforated catheter'slumen contacts the sensor's electroactive surfaces.

In still another embodiment, the catheter 12 includes at least a firstlumen and a second lumen. The sensor 14 is configured for insertion intothe catheter's first lumen. The second lumen can be used for infusionsinto the host's circulatory system or sample removal without disturbingthe sensor within the first lumen.

FIGS. 2A-2F are schematic views of a sensor integrally formed(integrally incorporated) onto a surface of a catheter, in someexemplary embodiments. In some embodiments, the sensor can be integrallyformed on an exterior surface 232 of the catheter. In other embodiments,the sensor can be integrally formed on an interior surface of thecatheter (e.g., on a lumenal surface). In still other embodiments, thesensor can be integrally formed on the sensor's tip (e.g., as indicatedby 214 a). In yet other embodiments, the sensor can be integrallyincorporated with the catheter, for example by bonding a sensor of thetype described in FIGS. 3A to 3C into an inner or outer surface of thecatheter.

In some embodiments, one or more of the electrodes is deposited on thein vivo portion of the catheter 212, such as via screen-printing and/orelectrospinning. In some embodiments, at least one of the electrodes240, such as but not limited to a counter and/or a reference electrodeis deposited within the ex vivo portion of the catheter (e.g., withinthe connector/hub). In one embodiment, two working electrodes 240 aredisposed on the exterior surface 232 of the catheter's in vivo portion.The first working electrode is configured to generate a signalassociated with the analyte and with non-analyte-related species thathave an oxidation/reduction potential that overlaps with that of theanalyte. The second working electrode is configured to generate a signalassociated with non-analyte-related species that have anoxidation/reduction potential that overlaps with that of the analyte. Asdescribed elsewhere herein, the signals of the first and second workingelectrodes can be processed to provide a substantially analyte-onlysignal. Continuous analyte sensors including two working electrodes aredescribed in greater detail elsewhere herein, in U.S. Patent PublicationNo. US-2007-0027385-A1, U.S. Patent Publication No. US-2007-0213611-A1,U.S. Patent Publication No. US-2007-0027284-A1, U.S. Patent PublicationNo. US-2007-0032717-A1, U.S. Patent Publication No. US-2007-0093704-A1,and U.S. Patent Publication No. US-2008-0083617-A1, each of which isincorporated herein by reference in its entirety.

In some alternative embodiments, one or more analyte sensors aredisposed (e.g., deposited, formed) on the exterior surface of the invivo portion of the catheter. Each sensor can include one, two or moreworking electrodes. The electrodes can be configured as describedelsewhere therein. In some embodiments, the catheter 12 is configuredwith two or more analyte sensors, wherein each of the sensors isconfigured to detect a different analyte and/or a property of thesample, as described elsewhere herein. For example, in some embodiments,the sensors are configured to detect at least two analytes such as butnot limited to albumin, alkaline phosphatase, alanine transaminase,aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium,CO₂, chloride, creatinine, glucose, gamma-glutamyl transpeptidase,hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH,phosphorus, potassium, sodium, total protein, uric acid, a metabolicmarker, various drugs, various minerals, various metabolites, and thelike. In some embodiments, at least one of the sensors is configured todetect a property of the host's blood, such as but not limited to pH,oxygen tension, PCO₂, PO₂, temperature, hematocrit, and the like. Insome circumstances, one or more of the plurality of analyte sensor canbe configured as a back-up or redundant sensor to a first sensor, suchas to confirm the correct functioning of the first sensor. For example,two glucose sensors could be disposed within the connector, such thatthe second glucose sensor provides a confirmation of the first glucosesensor's measurements.

Generally, the sensor system is provided with a cap 32 that covers thecatheter and the in vivo portion of the integral sensor (e.g., see FIG.1C ₂). A needle or trochar that runs the length of the catheter supportsthe device during insertion into the host's blood stream. Prior to use,medical caregiver holds the device by the fluid connector 218 andremoves the cap to expose the in vivo portion of the device (e.g., thecatheter). The caregiver inserts the in vivo portion of the device intoone of the host's veins or arteries (depending upon whether the catheteris an intravenous catheter or an arterial catheter). After insertion,the needle is withdrawn from the device. The device is then capped orconnected to other medical equipment (e.g., saline bag, pressuretransducer, blood collection bag, total parenteral feeding, dialysisequipment, automated blood chemistry equipment, etc.). In somealternative embodiments, the sensor-integrated catheter can be incommunication (e.g., fluid communication) with the host's vascularsystem through a vascular access device.

In some embodiments, an analyte sensor system includes a sensingmechanism substantially similar to that described in U.S. PatentPublication No. US-2006-0020187-A1, which is incorporated herein byreference in its entirety; for example, with platinum working electrodeand silver reference electrode coiled there around. Alternatively, thereference electrode can be located remote from the working electrode soas not to be inserted into the host, and can be located, for example,within the fluid coupler 20, thereby allowing a smaller footprint in theportion of the sensor adapted for insertion into the body (e.g., bloodstream); for example, without a coiled or otherwise configured referenceelectrode proximal to the working electrode. Although a platinum workingelectrode is discussed, a variety of known working electrode materialscan be utilized (e.g., Platinum-Iridium or Iridium). When locatedremotely, the reference electrode can be located away from the workingelectrode (e.g., the electroactive portion) at any location and with anyconfiguration so as to maintain bodily and/or in fluid communicationtherewith as is appreciated by one skilled in the art.

In an alternative embodiment, the sensor tip 14 a includes an enlarged,atraumatic area, for example a dull or bulbous portion about two timesthe diameter of the sensor or larger. In one exemplary embodiment, theenlarged portion is created by heating, welding, crushing or bonding asubstantially rounded structure onto the tip of the sensor (e.g.,polymer or metal). In another exemplary embodiment, the tip of thesensor is heated (e.g., arc welded or flash-butt resistance welded) tocause the tip to enlarge (e.g., by melting). The enlarged portion can beof any atraumatic shape, such as but not limited to oval, round,cone-shaped, cylindrical, teardrop, etc. While not wishing to be boundby theory, it is believed that an atraumatic or enlarged area enablesenhanced stability of a small diameter sensor in the blood flow andensures that the sensor remains within the blood flow (e.g., to avoidpiercing a vessel wall and/or becoming inserted subluminally.)

In some embodiments, one or more additional working electrodes can beprovided on the sensor for measuring baseline, and thereby subtractingthe baseline from the first working electrode to obtain a glucose-onlysignal and/or to measure additional analytes, as disclosed in copendingU.S. Patent Publication No. US-2005-0143635-A1, U.S. Patent PublicationNo. US-2007-0027385-A1, U.S. Patent Publication No. US-2007-0213611-A1,and U.S. Patent Publication No. US-2008-0083617-A1, all of which areherein incorporated by reference in their entirety.

Referring now to FIGS. 2A-2E in more detail, some embodiments of theanalyte sensor system include a catheter 212 adapted for inserting intoa host in a hospital or clinical setting, wherein the analyte sensor 214is built integrally with the catheter 212. For example, a glucose sensorcan be integrally formed on the catheter itself. FIGS. 2A-2B illustrateone embodiment, wherein the catheter 212 is configured both forinsertion into a host, and can be configured to couple to other medicaldevices on its ex vivo end. However, coupling to other medical devicesis not necessary. In some embodiments, the catheter includes a connector218 configured for connection to tubing or other medical devices, asdescribed herein. The embodiment shown in FIGS. 2A-2B includes two orthree electrodes 240 on the outer surface of the in vivo portion of thecatheter 212. In some embodiments, the catheter is perforated (asdescribed elsewhere herein) and at least one electrode is disposedwithin the lumen (not shown) of the perforated catheter. In someembodiments, the catheter includes a single lumen. In other embodiment,the catheter includes two or more lumens.

With reference to FIGS. 2C-2E, in some embodiments, at least one workingelectrode 240 is disposed on the exterior surface of the in vivo portionof the catheter. Alternatively, the at least one working electrode canbe disposed on an interior surface of the catheter, on the tip of thecatheter, extend from the catheter, and the like. In general, thepreferred embodiments can be designed with any number of electrodes,including one or more counter electrodes, one or more referenceelectrodes, and/or one or more auxiliary working electrodes. In furtherembodiments, the electrodes can be of relatively larger or smallersurface area, depending upon their uses. In one example, a sensorincludes a working electrode and a reference electrode that has a largersurface area (relative to the surface area of the working electrode) onthe surface of the catheter. In another example, a sensor includes aworking electrode, a counter electrode, and a reference electrode sizedto have an increased surface area as compared to the working and/orcounter electrode. In some embodiments, the reference electrode isdisposed at a location remote from the working electrode, such as withinthe connector (e.g., coiled within the connector). In some embodiments,the reference electrode is located on the host's body (e.g., in bodycontact).

The electrodes 240 can be deposited on the catheter using any suitabletechniques known in the art, for example, thick or thin film depositiontechniques. The electrodes can be formed of any advantageous electrodematerials known in the art (e.g., platinum, platinum-iridium, palladium,graphite, gold, carbon, silver, silver-silver chloride, conductivepolymer, alloys, combinations thereof, and the like). In otherembodiments, one or more of the electrodes is formed from anelectrically conductive material (e.g., wire or foil comprisingplatinum, platinum-iridium, palladium, graphite, gold, carbon, silver,silver-silver chloride, conductive polymer, alloys, combinationsthereof, and the like) applied to the exterior surface of the catheter,such as but not limited twisting, coiling, rolling or adhering.

In some embodiments, the catheter is (wired or wirelessly) connected tosensor electronics (not shown, disposed on the catheter's connectorand/or remote from the catheter) so as to electrically connect theelectrodes on the catheter with the sensor electronics. The insertedcatheter (including the sensor integrally formed thereon) can beutilized by other medical devices for a variety of functions (e.g.,blood pressure monitor, drug delivery, etc).

Referring now to FIGS. 2G through 2S, in some preferred embodiments aplurality of analyte sensors 240 are disposed within a widened portionof the catheter, such as but not limited to a flared portion and/or aconnector portion 212, or within the interior of a connector 250, suchas but not limited to a Leur lock, a Y-connector, a T-connector, anX-connector, and a valve, wherein a first side/end of the connector isconfigured to be coupled and/or connected to another vascular accessdevice, such as a catheter or cannula, and a second side (e.g., end) ofthe connector is configured to be coupled/connected to other IVequipment, such as another connector, a valve, IV tubing, and the like.

FIG. 2G is a cross section of a vascular access device including aplurality of analyte sensors 240 in one embodiment. The vascular accessdevice, such as a catheter includes an in vivo portion configured forinsertion into a circulatory system of the host, including a lumen 212a, and a connector 218 having a wall 260 defining a duct 218 b. In someembodiments, an inner diameter of the connector is greater than an innerdiameter of the in vivo portion. For example, in some embodiments, thevascular access device is a 20-gauge or smaller catheter. In someembodiments, the in vivo portion of the catheter is configured andarranged for insertion into a circulatory system of a pediatric host,such as but not limited to a neonatal host. The vascular access deviceis configured and arranged for receipt of a sample of a bodily fluid ofa host (e.g., blood after catheter insertion). At the proximal end, alsoreferred to herein as the in vivo portion, the vascular access deviceincludes a catheter 212 having a lumen 212 a and a small orifice 212 b.At the distal end, also referred to here as the ex vivo portion, thevascular access device includes a connector 218, also referred to hereinas the “hub.” The hub includes an orifice 218 c, which is configured forconnection (e.g., fluid communication) with other IV equipment, such asvia one or more flanges 218 a. The connector 218 also includes a duct218 b, also referred to a widened portion (as compared to lumen 212 a,which may be referred to as the connector's lumen. A plurality ofanalyte sensors 240 is disposed within the duct 218 b. In someembodiments, the device includes an analyte sensor 240, wherein at leasta portion of the analyte sensor is located in the lumen or duct, suchthat the analyte sensor is located within about 60, 55, 50, 45, 40, 35,30, 25, 20, 15, 10, 5, 4, 3, 2, or 1-mm or less from a source of thebiological sample. For example, in some embodiments, the electroactivesurfaces are within about 40-mm or less of the blood prior to drawingthe blood back into the hub of an implanted catheter or into a fluidcoupler connected to an implanted catheter. In some embodiments, theanalyte sensor is located within about 30-mm or less from a source ofthe sample. Configuring the system such that the analyte sensor(s)(e.g., the electroactive surfaces of the electrodes) are located withinonly 60-mm or less from the sample (e.g., prior to drawing back thesample into the catheter) translates into a requirement for only verysmall sample volumes. For example, in some embodiments, the device isconfigured such that the analyte sensor is bathed in the sample when (nomore than) about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50,25, 15, 10, or 5-μl or less of the bodily fluid (e.g., blood) is drawnback. In some embodiments, one or more of the analyte sensors 240 isdeposited and/or formed on a surface of the duct 218 b, such as byscreen printing or other useful deposition techniques. In someembodiments, one or more of the analyte sensors 240 is applied to theduct's surface, such as by adhering or micro welding a previously formedsensor to the duct's surface. In some embodiments, at least a portion ofone or more of the analyte sensors 240 is unattached to the duct'ssurface. The analyte sensors can be configured to detect one or moreanalytes using any means known in the art, such as but not limited toelectrochemical detection, enzymatic detection, chemical detection,physical detection, immunochemical detection, optical detection,radiometric detection, and combinations thereof. For example, in oneembodiment of a device including three sensors 240 within the hub 218, afirst sensor 240 is configured to detect glucose electrochemically, asecond sensor 240 is configured to detect oxygen optically, and thethird sensor 240 is configured to detect bilirubin immunochemically.

In one exemplary embodiment, a system configured to measure one or moreanalytes in a host is provided, wherein the system includes a vascularaccess device including a first portion configured for insertion into ahost and a second portion configured to remain outside the host afterinsertion of the first portion; at least one analyte sensor 240 locatedwithin the second portion of the vascular access device, such that theat least one analyte sensor is exposed to a biological sample when thebiological sample is drawn back about 40-mm or less, when the vascularaccess device is in fluid communication with a circulatory system of thehost; and a flow control device configured to regulate exposure of theat least one sensor to a biological sample and to a reference solutionaccording to a flow profile. In some embodiments, the system isconfigured such that the at least one analyte sensor is exposed to thebiological sample when about 300-μl or less of the biological sample isdrawn back. In another embodiment, the system is configured such thatthe at least one analyte sensor is exposed to the biological sample whenabout 200-μl or less of the biological sample is drawn back. In someembodiments, the vascular access device includes a catheter. Forexample, in some embodiments, the catheter is 22-gauge or smaller. Insome embodiments, a lumen of the second portion is wider than a lumen ofthe first portion. For example, the lumen (e.g., duct) of a catheter hubis wider than the lumen of the in vivo portion of the catheter, inexemplary embodiments. In some embodiments, the second portion includesa connecting end on the catheter. For example, the second end of thecatheter (e.g., the hub) is configured and arranged for connection totubing (e.g., IV tubing, the tubing assembly). In other embodiments, thesecond portion includes a fluid coupler, wherein the fluid coupler isconfigured to releasably mate with a catheter. In some embodiments, theat least one sensor is incorporated into the second portion (e.g., theex vivo portion of the catheter), such as on an inner surface of thesecond portion. In some embodiments, at least a portion of the at leastone sensor is disposed in an orientation substantially parallel to alongitudinal axis of the second portion. In some embodiments, at least aportion of the at least one sensor is disposed in an orientationsubstantially perpendicular to a longitudinal axis of the secondportion. In some embodiments, the at least one sensor includes anexposed electroactive surface area with a dimension substantially equalto a width of a lumen of the second portion. In some embodiments, theexposed electroactive surface area intersects the lumen of the secondportion. In some embodiments, the at least one analyte sensor includesat least three analyte sensors located within the second portion of thecatheter. In a further embodiment, the at least one analyte sensorincludes at least eight analyte sensors located within the secondportion of the catheter. In some embodiments, the second portion isconfigured to provide identification information associated with a flowprofile, such as described elsewhere herein. In some embodiments, thesystem is configured to program the flow profile (of a flow controldevice) in response to automatic receipt of the identificationinformation. In some embodiments, the identification information isprovided by a mechanical structure of the second portion (e.g., thecatheter). In some embodiments, the identification information isprovided by electronics of the second portion (e.g., the catheter).

In another exemplary embodiment, a system configured to measure one ormore analytes in a host is provided, wherein the system includes a fluidcoupler including a first end and a second end, wherein the first end isconfigured to releasably mate with a connecting end of a catheter, andwherein the second end is configured to releasably mate with a tubingassembly; and at least one analyte sensor located within the fluidcoupler such that when the fluid coupler is mated to a catheter insertedinto a circulatory system of a host, the at least one analyte sensor isexposed to a biological sample when the biological sample is drawn backabout 40-mm or less. In one embodiment, the at least one sensor islocated on an inner surface of the fluid coupler. In some embodiments,the at least one sensor is incorporated into the fluid coupler. In afurther embodiment, the at least one sensor is disposed within a lumenof the fluid coupler (e.g., the second portion). In some embodiments,the system is configured such that the at least one analyte sensor isexposed to the biological sample when about 300-μl or less of thebiological sample is drawn back. In another embodiment, the system isconfigured such that the at least one analyte sensor is exposed to thebiological sample when about 200-μl or less of the biological sample isdrawn back. In some embodiments, the at least one sensor is incorporatedinto the fluid coupler. In some embodiments, the at least one sensor islocated on an inner surface of the fluid coupler. In some embodiments,the at least one sensor is disposed within a lumen of the fluid coupler.The at least one analyte sensor can be disposed in an orientationsubstantially parallel to a longitudinal axis of the fluid coupler, orin an orientation substantially perpendicular to the longitudinal axisof the fluid coupler. In some embodiments, the at least one sensorincludes an exposed electroactive surface area with a dimensionsubstantially equal to a width of a lumen of the fluid coupler, such asdescribed with reference to FIGS. 2M-2P. In some further embodiments,the exposed electroactive surface area intersects the lumen of the fluidcoupler. In preferred embodiments, the fluid coupler is configured toprovide identification information associated with a flow profile, suchas described with reference to FIG. 10E, herein. For example, in oneembodiment, the system is configured to program the flow profile of theflow control device in response to automatic receipt of theidentification information. In some embodiments, the identificationinformation is provided by a mechanical structure of the fluid coupler.For example, in some embodiments, a portion of the fluid coupler isconfigured to form a mechanical interlock with a portion of the flowcontrol device and/or the tubing assembly, wherein formation of themechanical interlock automatically selects a flow profile associatedwith the fluid coupler (or with a catheter size, with a type of host(e.g., infant host versus child host versus adult host) and the like).In some other embodiments, the fluid coupler includes electronics thatprovide identification information. In still other embodiments, thefluid coupler includes both a mechanical structure and electronicsconfigured to provide the identification information associated with theflow profile. In some embodiments, the fluid coupler includes multiplelumens, wherein the system is configured and arranged to infuse a fluida fluid in a first lumen of the fluid coupler, and to draw back abiological sample into a second lumen of the fluid coupler. Forexamples, in embodiments wherein the at least one analyte sensor islocated in the second lumen, a hydration, nutrition and/or medicamentsolution can be infused via the first lumen without substantiallyaffecting the at least one sensor. In some embodiments, the system isconfigured to infuse another solution, such as a calibration, wash orhydration solution through the second lumen of the fluid coupler, suchas for washing the sensor and/or for making reference measurements.While some embodiments include a single analyte sensor located in thefluid coupler, in other embodiments, the at least one analyte sensorincludes at least 2, 3, 4, 5, 6, 7, 8, or 9 or more analyte sensors. Insome embodiments, two or more of the analyte sensors are configured todetect the same analyte, such as for a back-up (e.g., in case a firstsensor fails the other sensor can be used) and/or as a quality check(e.g., to make sure the sensors are working substantially the same). Inother embodiments, the analyte sensors are each configured to measure adifferent analyte. In still other embodiments, some of the analytesensors are configured to detect the same analyte, while the remaininganalyte sensors are configured to detect different analytes. One skilledin the art appreciates the variety of possible analyte sensorconfiguration combinations.

In some embodiments, the system is configured and arranged such that theat least one analyte sensor is located within about 35, 30, 25, 20, 15,10, 5, 4, 3, 2, or 1-mm or less from a source of the biological sample.In some embodiments, the at least one analyte sensor is located (e.g.,within the vascular access device), such that the analyte sensor isbathed in the sample when about 1000, 900, 800, 700, 600, 500, 400, 300,200, 100, 50, 25, 15, 10, or 5-μl or less of the bodily fluid (e.g.,blood) is drawn back. In some embodiments, a lumen of the second portionis wider than a lumen of the first portion. For example, the lumen ofthe fluid coupler is wider than the lumen of the catheter. In someembodiments, the second portion is a fluid coupler, wherein the fluidcoupler is configured to releasably mate with the catheter. In someembodiments, the at least one sensor is incorporated into the secondportion. For example, in one embodiment, the at least one sensor islocated on an inner surface (e.g., the lumenal surface) of the fluidcoupler (e.g., the second portion). In a further embodiment, the atleast one sensor is disposed within a lumen of the fluid coupler (e.g.,the second portion). In some embodiments, at least a portion of the atleast one sensor is disposed in an orientation substantially parallel toa longitudinal axis of the fluid coupler (e.g., the second portion). Insome embodiments, at least a portion of the at least one sensor isdisposed in an orientation substantially perpendicular to a longitudinalaxis of the fluid coupler (e.g., the second portion). In someembodiments, the at least one sensor includes an exposed electroactivesurface area with a dimension substantially equal to a width of a lumenof the fluid coupler (e.g., the second portion). In some embodiments,the exposed electroactive surface area intersects the lumen of the fluidcoupler (e.g., the second portion). In some embodiments, the fluidcoupler (e.g., the second portion) is configured to provideidentification information associated with the flow profile. In someembodiments, the system is configured to program the flow profile of theflow control device in response to automatic receipt of theidentification information (e.g., via a wired or wireless connectionand/or triggered by a physical and/or operable connection of thevascular access device (e.g., fluid coupler and/or catheter) with theflow control device and/or system electronics). In some embodiments, theidentification information is provided by a mechanical structure of thefluid coupler (e.g., the second portion). In some embodiments, theidentification information is provided by electronics of the fluidcoupler (e.g., the second portion).

In some embodiments, the at least one analyte sensor is configured tomeasure an analyte selected from the group consisting of albumin,alkaline phosphatase, alanine transaminase, aspartate aminotransferase,bilirubin, blood urea nitrogen, calcium, CO₂, chloride, creatinine,glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactatedehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium,total protein, uric acid, a metabolic marker and a drug. In someembodiments, the at least one analyte sensor includes at least threeanalyte sensors located within the second portion of the vascular accessdevice and configured to measure at least three analytes. For example,in one embodiment the second portion of the vascular access device isthe second portion of a catheter (e.g., the ex vivo portion, the hub),and the at least three analyte sensors are located therein. In someembodiments, the at least one analyte sensor includes at least eightanalyte sensors located within the second portion of the vascular accessdevice (e.g., the fluid coupler or the second portion (e.g., hub or exvivo portion) of a catheter) and configured to measure at least eightanalytes.

In one exemplary embodiment, the catheter is a peripheral catheter(e.g., for insertion into a vein located in an arm and/or leg) havingthe analyte sensor located within the catheter hub. In some embodiments,the volume that the catheter hub can hold has been restricted (e.g.,reduced), such as by fabricating the catheter hub with a reducedinternal diameter. In this embodiment, the sample is drawn back onlyabout 50, 45, 40 or 35-mm (e.g., into the catheter hub, depending uponthe length of the catheter), such that the analyte sensor is bathed inthe sample.

In yet another exemplary embodiment, the analyte sensor is locatedwithin the lumen of a fluid coupler (e.g., configured for fluidconnection with a catheter). In this embodiment, when the fluid coupleris coupled to an implanted peripheral catheter, the sensor's electrodesare bathed in a sample when the sample is drawn back a distance of about50, 45, 40, 35 or 30-mm, depending upon the length of the catheter,which correlates with a sample volume of about 500, 450, 400, 350, 300or 250-μl or less.

Alternatively, when the catheter is coupled to a central catheter (e.g.,a catheter for insertion into vessels in the body, such as to access theheart), the distance the sample is drawn back (e.g., to sufficientlycontact/bathe the electrodes such that analyte measurements can betaken) is much farther (e.g., relative to the distance of draw-back intoa peripheral catheter), since central catheters range from about 12 toabout 24-inches in length. Thus, in this exemplary embodiment, thedistance the sample is drawn back includes the entire length of thecentral catheter (including the catheter's hub) and a portion of theconnector, such as but not limited to about 12, 13, 14 or 15 inches, toabout 18, 19, 20, 21, 22, 23, 24 or 25-inches or more, depending uponthe length of the catheter, which can correspond with a sample volume ofabout 1.5-ml, 1.25-ml, 1-ml, 900-μl, 800-μl, 700-μl, 600-μl or 500-μl orless, depending upon the catheter's size and/or configuration, the fluidcoupler's configuration, and the like. If the sensor extends from thefluid coupler into the central catheter, the distance the sample isdrawn back is reduced to a portion of the central catheter's length,with a corresponding reduction in sample volume.

FIG. 2H is a cross section of a vascular access device including aplurality of analyte sensor 240 in another embodiment. In thisembodiment, the vascular access device is a connector 250 (e.g., fluidcoupler) and/or valve, such as but not limited to a Leur lock, aY-connector, a T-connector, and an X-connector. In general, theconnector 250 (e.g., fluid coupler) is configured to becoupled/connected to vascular access devices, such that a fluid can passbetween two vascular access devices coupled to the connector's two ends.For example, a first end of the connector can be coupled to a catheteror cannula implanted (e.g., pre-implanted) in a host's vein or artery,and a second end of the connector can be coupled to another connector, avalve, IV tubing, and IV bag, a test device, etc. In some embodiments,the connector 240 is a fluid coupler, such as described with referencefor FIGS. 1A-1M and 2M-2S. The connector includes a duct 254 (e.g.,lumen) and a proximal orifice 258. A plurality of analyte sensors 240 isdisposed within the duct 254. As described with reference to the deviceshown in FIG. 2G, the plurality of analyte sensors can be disposedwithin the duct 254 using any means known in the art. In someembodiments, one or more of the analyte sensors are deposited (e.g.,formed) on a surface of the duct 254 (e.g., on an interior surface). Insome embodiments, one or more of the analyte sensors are applied to thesurface of the duct 254. In some embodiments, one or more of the analytesensors is configured to pass through (e.g., intersect) the wall 252 ofthe connector such that a first portion of the sensor 240 is disposedwithin the duct 254 and a second portion of the sensor 240 is disposedat the exterior of the connector 250 (described in more detail herein).

FIG. 2I is a cross-section of a vascular access device of either FIG. 2Gor FIG. 2H taken along line 2I-2I, looking towards the proximal end ofthe vascular access device. The device includes a duct/lumen 212 b/254defined by a wall 260. The in vivo orifice (also referred to as theproximal orifice with relation to the host) of the device is representedby circle 212 b/258. As shown in this embodiment, a plurality of sensorscan be disposed within the duct, such as but not limited at the in theinterior surface of the wall. In some embodiments, the device includestwo analyte sensors. In some embodiments, the device includes 3, 4, 5,6, 7 or more analyte sensors. In some embodiments, one or more of theanalyte sensors are configured to be disposed entirely within the duct(e.g., to not protrude out of the duct). In some embodiments, one ormore analyte sensors can be configured such that a portion thereofprotrudes out the duct, such as but not limited to into the lumen of acatheter 212 or through the proximal orifice 212 b/258 of the device. Insome embodiments, a portion or one or more of the sensors can beconfigured to protrude through the ex vivo orifice (also referred to asthe distal orifice with ration to the host) of the device. The analytesensors 240 disposed within the device can be of any configuration andcan use any detection method, including but not limited toelectrochemical, enzymatic, optical, radiometric, chemical, physical,immunochemical and the like, including a combination thereof.

FIG. 2J is a cross-section of a vascular access device of either FIG. 2Gor FIG. 2H taken along line 2I-2I, looking towards the proximal end ofthe vascular access device, prior to installation of any analyte sensors240. FIG. 2K depicts the FIG. 2J device after sensor installation. Inthis embodiment, a plurality of sensor sites 262 is located at thesurface of the wall 260. While FIGS. 2J and 2K depict the sensor sites262 as being depressions in the wall 260, the sensor sites 262 can be ofany configuration, such as but not limited to a portion of the wall'sinner surface that is flush with the remaining portion of the innersurface, a textured portion of the inner surface, a channel, a hole, andthe like. In some embodiments, the sensor sites can have a plurality ofconfigurations. For example, in a device including four sensor sited262, a first site can have a first configuration, the second and thirdsites a second configuration, and the fourth site yet anotherconfiguration.

FIG. 2L is a cross-section of a vascular access device of either FIG. 2Gor FIG. 2H taken along line 2I-2I, looking towards the proximal end ofthe vascular access device, in an alternative embodiment. In thisembodiment, the sensor sites 262 can be formed to include a plug 264and/or a breakaway portion of the wall 260, which can be removed toenable sensor installation. For example, a plug/breakaway portion can bepushed and/or punched out of the sensor site and then the sensorinstalled in the sensor site. In some embodiments, removal of aplug/breakaway portion creates a channel through the wall, such that asensor (at least a portion thereof) can be inserted through the channeland into the duct 254. In some embodiments, the portion of an installedsensor remaining on the external side of the wall is configured tofunctionally connect to sensor electronics, as is appreciated by oneskilled in the art. While not wishing to be bound by theory, it isbelieved that this configuration enables increased accuracy and speed indevice assembly because the sensors can be manufactured separately fromthe device and then installed into the device in a “plug-and-play”fashion.

FIG. 2M illustrates another embodiment of the analyte sensor systemconfigured to measure one or more analytes in a bodily fluid of a host,namely a fluid coupler (e.g., connector) 250 having a wall 260, a lumen254, a first end 258 configured and arranged for fluid communicationwith a vascular access device, and a second end 256 configured andarranged for fluid communication with an infusion device, such as via IVtubing and/or a tubing assembly, such as described elsewhere herein. Theanalyte sensor 240 (e.g., 240 a, 240 b and/or 240 c) is configured andarranged to generate a signal associated with an analyte in a sample ofa circulatory system of a host (e.g., a bodily fluid such as but notlimited to blood), wherein at least a portion of the analyte sensor isdisposed within the lumen 254 of the fluid coupler 250. In preferredembodiments, the device is configured such that, when it is fluidlyconnected to an implanted catheter, at least a portion of the analytesensor 240 is located within about 60, 55, 50, 45, 40, 35, 30, 25, 20,15, 10, 5, 4, 3, 2, or 1-mm or less from the source of the sample, suchas from the tip of the inserted catheter. In some embodiments, theanalyte sensor is located within about 30-mm or less from a source ofthe sample. Advantageously, locating the sensor close to the source ofsample (e.g., bodily fluid, blood) and configuring the system for use ofvery small samples, including return of the sample to the host, limitsthe loss of blood from the host, thereby enabling the use of the devicein circumstances, such as neonatal and critical care settings, whereinloss of blood is a critical issue for host health and/or survival. Forexample, in one embodiment, the device is configured such that analytesensor is bathed in the sample when about 1000, 900, 800, 700, 600, 500,400, 300, 200, 100, 50, 25, 15, 10, or 5-μl of the bodily fluid is drawnback.

In some embodiments, the vascular access device (e.g., a catheter or afluid coupler) includes a longitudinal axis. For example, if the deviceis a catheter, the longitudinal axis can extend from the tip 212 b ofthe in vivo portion to the hub orifice 218 c. In another example, if thedevice is a fluid coupler, the longitudinal axis can extend from theproximal orifice 258 to the distal orifice 256. The analyte sensor(e.g., the electrodes, electroactive surfaces) can be disposed in thecatheter hub or fluid coupler lumen in various orientations withrelation to the longitudinal axis. For example, in some embodiments, theanalyte sensor is disposed in an orientation parallel to thelongitudinal axis. For example, in one embodiment, the analyte sensorintersects the wall 260, such that the electroactive surface(s) arelocated along an interior (e.g., luminal) surface of the wall. Forexample, the electrode can intersect the wall at two points that areseparated by a longitudinal distance on the wall, such that theelectroactive surface(s) are oriented parallel to the longitudinal axisof the device. For example, with reference to the device of FIG. 2M, inan alternative embodiment, one or more of the electrodes (e.g., 240 a,240 b and/or 240 c) can intersect the wall at two points along one sideof the device (e.g., 260 a or 260 b) such that the length of theelectrode runs parallel to the longitudinal axis of the device. Forexample, if the device includes three electrodes, the electrodes can bespaced about the inner circumference of the lumen, such as but notlimited to equidistant from each other, wherein each electrode runsparallel along the luminal wall in an orientation parallel to thelongitudinal axis of the device. In another embodiment, one or moresensors (e.g., twisted and/or bundled working and/or referenceelectrodes, instead of individual electrodes) can be placed in thedevice such that a length of the electroactive surfaces of the sensor(s)is parallel to the longitudinal axis of the device. For example, thedevice could include 2, 3, 4, 5 or more analyte sensors. In someembodiments, the reference electrode is disposed remotely from theworking and/or counter electrode(s). In some embodiments, one referenceelectrode is configured to function as the reference electrode for twoor more analyte sensors.

In some embodiments, the electrode(s) are disposed within the catheterhub or fluid coupler such that they are oriented perpendicularly to alongitudinal axis of the device. Returning again to the exemplaryembodiment illustrated in FIG. 2M, the device can be configured suchthat the individual electrodes (e.g., 240 a, 240 b and 240 c) intersectwall 260 on opposite sides (e.g., 260 a and 260 b) of the device, suchthat each electrode is perpendicular to the longitudinal axis of thefluid coupler. For example, in some embodiments, the first and secondpoints can be connected by a line that is perpendicular to thelongitudinal axis of the device. One skilled in the art appreciates thatwhile FIG. 2M illustrates individual electrodes 240 a, 240 b and 240 c,in other embodiments, one complete sensor (e.g., having bundled and/ortwisted working, counter and/or reference electrodes) can be used. Insome further embodiments, the device is configured such that theelectroactive surface of each electrode has a surface area having afirst dimension (e.g., length or width) substantially equal to adiameter of the lumen of the connector or hub. For example, in theembodiment shown in FIG. 2M, the length of the electroactive surfaces(e.g. window 343 of FIG. 3B) can be substantially equal to the innerdiameter of the fluid coupler. In a further example, each electrode canbe formed, including the membrane, as described herein, inserted throughthe wall(s) of fluid coupler (e.g., through holes or using a needle topierce the wall(s) formed of elastomeric material as described herein),such that the electroactive surface is disposed within the lumen, excesselectrode material removed from one side (e.g., 260 b) and thenelectrical connection with system electronics (e.g., via solderingelectrical wires) on the opposite side (e.g., 260 a).

While the electrodes of the embodiment illustrated in FIG. 2M aredisposed individually, additional configurations are contemplated in thepreferred embodiments. For example, in some embodiments, the electrodesare bundled and/or twisted, such that the electrodes intersect the walltogether. In other embodiments, the analyte sensor includes an electrodelocated within the lumen of the in vivo portion of the catheter, such asat the tip 212 b of the catheter. In another embodiment, the electrodeis located at and/or on the luminal surface of the in vivo portion ofthe catheter. For example, in some embodiments, the electrodes aredeposited on a flexible support, which is inserted into the lumen. Inanother example, in some embodiments, the electrodes are deposited onthe flexible support when the flexible support having a planarconfiguration, which is then cut to size, rolled into a cylindricalconfiguration (such that the electrodes are within the interior of thecylinder), and then inserted into the catheter lumen. In a furtherexemplary embodiment, the flexible support is formed of an appropriatematerial to form the in vivo portion of a catheter, electrodes areapplied to a surface of the material (e.g., when in a planarconfiguration) using methods known in the art, the material is cut tosize, rolled and the cut edges sealed (e.g., by welding or an adhesive),and a catheter hub applied thereto, such that the rolled and sealedflexible support forms the wall of the in vivo portion of the catheter,wherein the electrodes are located on the luminal surface of theelectrode wall. Forming the catheter and electrodes in this mannerenables easy manufacturing techniques and a variety of electrodeconfigurations, such as but not limited to linear electrodes, circularelectrodes, electrodes that spiral along/around the interior of thecatheter, and the like. In additional embodiments, a plurality ofanalyte sensors (e.g., including two or more electrodes) can be disposedin the catheter lumen, such that two or more analytes can be measured,or such that redundant sensors (e.g., two or more glucose sensors) canmeasure a single analyte.

FIG. 2N illustrates an embodiment of a fluid coupler configured toinclude two or more analyte sensors, namely the fluid coupler is dividedinto two or more channels, each of which includes an analyte sensor. Inone illustrated embodiment, the fluid coupler is divided into two flowchannels 254 (e.g., two lumens), each with an analyte sensor disposedtherein (e.g., electrode 240 a, 240 b and 240 c). For example, theanalyte sensor in one flow channel can be configured to detect glucoseand the analyte sensor in the other flow channel can be configured todetect a cardiac marker, in one embodiment. In another illustratedembodiment, the fluid coupler is divided into three flow channels (e.g.,three lumens), each with an analyte sensor disposed therein. Inclusionof additional lumens enables incorporation of additional analyte sensorssuch that each analyte sensor receives a sample uncontaminated byreagents and/or products and/or for infusion of a medicament. Forexample, a glucose sensor using GOX to detect glucose generates H₂O₂,which can affect the other sensors of the device. If the sensors arelocated in separate lumens, the H₂O₂ generated by the glucose sensorcannot affect the sensors located in the other lumens. As a furtherexample, sample that is drawn back flows into each of the lumens, suchthat each of the sensors is bathed in sample uncontaminated by reagentsand reaction products from another of the sensors. When the device isflushed (e.g., with saline or calibrant solution), each of the sensorsare washed and does not contaminate another sensor with itsreagents/reaction products. Accordingly, in some embodiments, the fluidcoupler is divided into additional channels, such as a network of 4, 5,6, 7, 8, 9, 10 or more channels, such that panels of analytes can becontinuously measured at the same time. In some embodiments, the fluidcoupler is miniaturized, thereby providing a micro-scale, multi-sensordevice, such that about 5, 10, 15, 20, 25, 30, 40, 50, 100 or moreanalytes can be continuously monitored simultaneously. Thisconfiguration provides certain advantages, such as but not limited to,this device is amenable to high-throughput, modular manufacturing on anassembly line; the device can be connected to a wide variety ofcatheters currently in use; a plurality of sensors can be usedsimultaneously; and the device is amenable to custom-made analyte panels(e.g., Hospital #1 wants glucose and oxygen sensors, while Hospital #2wants glucose, creatinine and temperature sensors).

A variety of techniques can be used to manufacture an integrated fluidcoupler and analyte sensor device. For example, in some embodiments, thewall 260 is formed of a self-sealing material (not shown), such that theanalyte sensor can be inserted through the wall using a needle. Forexample, a needle containing the sensor in its barrel can be insertedthrough the wall, followed by withdrawal of the needle over the sensor,such that the sensor remains inserted through the wall. For example,polymer tubing, such as but not limited to silicone tubing, can be usedto form the central body of a fluid coupler, and connector ends (e.g.,configured for connecting the fluid coupler to a catheter and/or tubing)attached thereto. Additional methods of manufacturing the preferredembodiments are detailed in the section entitled “Multi-SensorApparatus.”

FIGS. 2O and 2P illustrate another method of manufacturing an integratedfluid coupler and analyte sensor device, such as that shown in FIG. 2M.In one embodiment, the fluid coupler is formed of two or more mateableportions (e.g., 260-1, 260-2), wherein the first and second mateableportions are configured and arranged to form a seal 260 e when matedtogether, such that the lumen is formed 254. For example, the twomateable portions can be formed by injection molding a suitablemedical-grade plastic. In the embodiment shown in FIG. 2O, the twomateable portions 260-1, 260-2 are configured to mate together, such asbut not limited to in a clam shell configuration. One or both of the twomateable portions 260-1, 260-2 includes an indentation 260 c on thesealing edge(s) (e.g., mating edges) configured to receive an analytesensor (and/or an electrode). In the illustrated embodiment, the twomateable portions each include three indentations, wherein theindentations are configured to receive the electrodes 240. In someembodiments, the sensor electrodes are inserted separately (e.g., asopposed to in a bundled or twisted configuration). In a furtherembodiment, the electrodes can be spaced along the length of the lumento optimize fluid flow and analyte detection. For example, in someembodiments, the electrodes are spaced equally within the lumen (e.g.,the distance between electrodes 240 a and 240 b is substantially equalto the distance between electrodes 240 b and 240 c). In someembodiments, the device is configured such that the diameter of thelumen is substantially the same as the length of the electroactivesurfaces (e.g., which span the lumen). Additional configurations arecontemplated, such as non-linear spacing and non-equal spacing of theelectrodes.

Referring again to FIGS. 2O and 2P, in some embodiments, a grommet 260 dcan be included at the point at which the electrode intersects the matedwall. In other embodiments, the wall surrounding the electrode (e.g., at260 d) can be welded, to form a seal between the electrode and the wall.In some embodiments, the seal is fluid-tight. In some embodiments, aportion of the wall material is melted by the welding, such that aportion of the melted wall material can soak into the membrane of theelectrode. FIG. 2P illustrates an alternative method of forming theintegrated fluid coupler and analyte sensor device, wherein the twomateable portions 260-1, 260-2 comprise cylinders configured to matetogether such that the analyte sensor 240 spans the lumen 254.

A connection between the analyte sensor (and/or individual electrodes)and sensor electronics can be made on the exterior surface of the fluidconnector. For example, in some embodiments, the analyte sensorelectrodes are soldered to wires, which in turn make electricalconnection with the sensor electronics. In other embodiments, theelectrodes are clipped off substantially flush with the exterior surfaceof the wall and a PCB 20 t (e.g., configured to make suitable electricalconnection with each of the electrodes) is attached to the clipped-offends of the electrodes (e.g., via adhesive or welding), such that theelectrical connections are made; the PCB is then used to connect thesensor to sensor electronics. In still other embodiments, elastomericcontacts can be used to make a connection between the electrodes andsensor electronics, in a manner similar to that illustrated in FIGS. 1Hand 1J. Additional methods of connecting analyte sensors to sensorelectronics are appreciated by those skilled in the art.

FIG. 2Q illustrates an alternative embodiment of an integrated fluidcoupler and analyte sensor device, in which the electrodes are formed ofconductive elastomeric material (e.g., contacts 240). A portion of thefluid coupler can be configured with one or more holes 260 c to receivethe elastomeric contacts. For example, the fluid coupler can beinjection molded of plastic, including the holes 260 c configured toreceive the elastomeric contacts 240. The electrode/elastomeric contactscan be formed of any conductive elastomeric materials, such as but notlimited to carbon black elastomer. Each elastomeric contact isconfigured with an interior side 240 e and an exterior side 240 d. Theinterior side is configured and arranged as an electrode, such as one ormore working electrodes (plus and/or minus enzyme), a counter electrodeor a reference electrode, as described elsewhere herein. The exteriorside is configured and arranged for electrical connection with thesensor electronics. The electrode/elastomeric contact can have anyuseful shape, such that the interior side can be inserted through a holeof the fluid coupler, such that the electroactive surface can be bathedby a sample drawn back into the fluid coupler, and such that theexterior side is sufficiently exposed for making the electricalconnection with the sensor electronics. The conductive material can beformed into any shape. For example, the electrode/elastomeric contactcan be a ball, or wedge or cylinder. In the embodiment shown in FIG. 2Q,the electrode/elastomeric contact includes a cylindrical body with aflat electroactive surface at the interior side 240 e, and sloped orflared sides. The interior side 240 e is configured and arranged to besubstantially flush with the lumenal surface of the fluid conduit wall,such that fluid turbulence, biofouling and/or clotting is/aresubstantially reduced when the device is in use. The exterior side 240 dincludes a flat butt end, which is somewhat larger in diameter thancylindrical body, and a shoulder. In some embodiments, the elastomericmaterial is sufficiently pliable that the elastomeric contact canconform to the structure of the hole, when it is inserted into the hole;such that it makes a substantially water-tight seal with the wall of thefluid coupler. For example, in the illustrated embodiments, the flaredsides are configured to conform to the hole (e.g., an interference fit),such that the conformed side and the shoulder make a water-tight sealwith the wall of the fluid conduit.

Electrical connection between the electrode/elastomeric contacts 240 andsensor electronics can be made with their exterior surfaces by anymethod known in the art. For example, in some embodiments, a PCB 20 tconfigured and arranged for electrical contact with the elastomericcontacts is adhered over the elastomeric contacts. A cover, such as oneconfigured with a female connector 20 n (e.g., see cover 20 k in FIGS.1H-1J) is adhered over the PCB, or the PCB is hard-wired to anelectrical cable. In another embodiment, the electrode/elastomericcontacts are simply soldered to the wires of an electrical cable. Instill other embodiments, conductive traces (e.g., vias) is applied tothe exterior surface of the fluid conduit (e.g., prior to insertion ofthe electrode/elastomeric contacts) such that when the elastomericcontacts are inserted into the holes, the shoulder of eachelectrode/elastomeric contact makes an electrical connection with one ofthe conductive traces. The electrical traces, in turn, make electricalconnections with sensor electronics, as is known to one skilled in theart.

Use of electrode/elastomeric contacts 240 enables unique manufacturingmethods which are amenable to high through-put, modular manufacturing.In one embodiment, the individual electrode/elastomeric contacts areformed and then processed in batches, such as to deposit theelectroactive surfaces and membranes on the interior surfaces. Forexample, to prepare a batch of working electrode/elastomeric contacts, abatch of unprepared elastomeric contacts (e.g., 100, 1000, etc.) can beplaced, head-up, in a holder. Platinum or other conductive electrodematerial can then be deposited on the heads, sides and/or entireelectrode/elastomeric contacts using suitable means such aselectroplating, electrospinning, spraying, and the like, to form theelectroactive surfaces. A membrane is applied as one or more layers,using known thin-film or thick-film techniques. To form referenceelectrode/elastomeric contacts, Ag/AgCl particles or other conductiveelectrode material can be mixed or otherwise formed in or on thematerial used to form the electrode/elastomeric contacts, or Ag/AgCl canbe applied to the interior surfaces of the referenceelectrode/elastomeric contacts, for example.

In a another embodiment, the electrode/elastomeric contacts are formedby preparing a sheet of the elastomeric conductive material, preparing asurface of the sheet, such as forming an electroactive surface thereon,and then punching the individual electrode/elastomeric contacts from thesheet.

FIG. 2R is a cross-section of another embodiment of a fluid couplerincluding a continuous analyte sensor 240 disposed within the lumen 254.Namely, a central body 270 is inserted within the lumen. The centralbody includes conductive bodies 272 disposed within a non-conductivematerial. Each conductive body 272 includes a conductive member 273, formaking electrical contact with sensor electronics. The sensor electrodes240 are deposited on the conductive bodies 272, such that when thecentral body 270 is inserted into the lumen of the fluid coupler, theelectrodes are bathed in sample when the sample is drawn back. In someembodiments, the conductive members provide stabilization to the centralbody. In other embodiments, the central body and conductive members areconfigured and arranged such that the lumen is divided into a pluralityof chambers (e.g., smaller lumens), such that a plurality of analytesensors are deposited on the conductive bodies and such that eachanalyte sensor contacts a separate sample (e.g., uncontaminated byreagents or reaction products from an analyte sensor in anotherchamber). In one embodiment, the central body is configured as anelongated core, such as but not limited to a cylindrical core. In someembodiments, the central body 270 is configured as a plurality ofconductive bodies 272, which run the length of the central body, bundledin a dielectric material, wherein the conductive members 273 extend outan end of the central body (e.g., rather than out the sides as shown inFIG. 2R). In this embodiment, a plurality of analyte sensors can bedeposited on the conductive bodies, wherein the central body is insertedinto the lumen of the fluid coupler.

FIG. 2S illustrates yet another embodiment of an analyte sensor disposedin a fluid coupler, including an electrode support 280 having one ormore analyte sensors 240 deposited thereon. The electrode support 280 isconfigured and arranged to optimize fluid flow there around and tosubstantially reduce biofouling and/or clotting thereon. For example, insome embodiments, the electrode support 280 is cigar or football shaped.The electrodes can be working, counter and/or reference electrodes. Insome embodiments, the electrode support 280 is stabilized by stabilizers282. While the stabilizers 282 shown in FIG. 2S are “fin” shaped, avariety of other shapes, such as projections, extensions, detents, andthe like can be used. In preferred embodiments, the stabilizerssubstantially maintain the electrode support 280 within the fluid streamsuch that the electrode support 280 is substantially immobile, such thatthe flow of fluid about the electrode support 280 is substantially even(e.g., the same rate there around).

In some embodiments, the device is formed by injection molding, usingtechniques known in the art. In one exemplary embodiment, the sensorsare placed in a mold, which is configured to hold the sensors in such anorientation that after the injection molding procedure, the sensors willbe in the correct location and/or orientation for correct function ofthe device. After the sensors are placed in the mold, the mold is closedand injected with a material (e.g., molten plastic). During theinjection molding process, the wall 260 of the device is thus formedabout a portion of each sensor 240, such that a sensing portion of eachsensor (e.g., electroactive surface) will be disposed within the duct212 b/258 and another portion of each sensor (e.g., a portion configuredfor connection to sensor electronics) will be disposed at the exteriorof the device. Similar manufacturing techniques are used for themanufacture of syringes and lancets, wherein the plastic portion of thedevice is formed about a portion of the needle.

In a medical setting, a variety of vascular access devices can besimultaneously made available for use in conjunction with a flow controldevice, as described elsewhere herein. As is understood by one skilledin the art, each vascular access device can require a unique flowprofile, such that the flow control device infuses and draws back thecorrect amounts of fluid and/or sample, at the correct time and for thecorrect lengths of time, to enable optimal sensor operation. In somecircumstances, a caretaker may select the wrong flow profile for aninstalled vascular access device; a medical error that might harm thepatient. Accordingly, in some embodiments, the vascular access device isconfigured and arranged to provide identification information to flowcontrol device, wherein the identification information is associatedwith the flow profile. For example, in some embodiments theidentification information is provided by a mechanical structure (e.g.,an engageable mechanical interlock wherein the vascular access deviceincludes one of two portions of the mechanical interlock and the flowcontrol device includes the second of the two portions of the mechanicalinterlock). In some embodiments, the identification information isprovided by electronics of the vascular access device (e.g., a bar code(e.g., identified by a bar code scanner incorporated into the flowcontrol device), an RFID chip configured for communication with theelectronics of the vascular access device and the like). In somepreferred embodiments, a flow profile associated with the vascularaccess device is initiated by the flow control device, afteridentification of the vascular access device via the identificationmodule. In preferred embodiments, the system is configured to programthe flow profile of the flow control device in response to automaticreceipt of the identification information (e.g., transmission of theidentification information without required user interaction). In thisembodiment, because the user does not enter which flow profile to usewith the vascular access device, user error is reduced, which in turnincreases patient safety.

While not wishing to be bound by theory, a number of the systems andmethods disclosed in the preferred embodiments (e.g., an analyte sensorto be disposed in communication with the host's blood), can be employedin transcutaneous (e.g., transdermal) or wholly implantable analytesensor devices. For example, the sensor could be integrally formed onthe in vivo portion of a subcutaneous device or a wholly implantabledevice. As another example, an enlarged surface area (e.g., bulbous end)can useful in the design of a transcutaneous analyte sensor.

Exemplary Sensor Configurations

Referring to FIGS. 3A to 3C, in some embodiments, the sensor can beconfigured similarly to the continuous analyte sensors disclosed inco-pending U.S. Patent Publication No. US-2007-0197889-A1 hereinincorporated by reference in its entirety. The sensor includes a distalportion 342, also referred to as the in vivo portion, adapted forinsertion into the catheter as described above, and a proximal portion340, also referred to as an ex vivo portion, adapted to operably connectto the sensor electronics. Preferably, the sensor includes two or moreelectrodes: a working electrode 344 and at least one additionalelectrode, which can function as a counter electrode and/or referenceelectrode, hereinafter referred to as the reference electrode 346. Amembrane system is preferably deposited over the electrodes, such asdescribed in more detail with reference to FIGS. 3A to 3C, below.

FIG. 3B is an expanded cutaway view of a distal portion of the sensor inone embodiment, showing working and reference electrodes. In preferredembodiments, the sensor is formed from a working electrode 344 (e.g., awire) and a reference electrode 346 helically wound around the workingelectrode 344. An insulator 345 is disposed between the working andreference electrodes to provide electrical insulation therebetween.Certain portions of the electrodes are exposed to enable electrochemicalreaction thereon, for example, a window 343 can be formed in theinsulator to expose a portion of the working electrode 344 forelectrochemical reaction.

In preferred embodiments, each electrode is formed from a fine wire witha diameter of from about 0.001 inches or less to about 0.050 inches ormore, for example, and is formed from, e.g. a plated insulator, a platedwire, or bulk electrically conductive material. For example, in someembodiments, the wire used to form a working electrode is about 0.002,0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.015, 0.020,0.025, 0.030, 0.035, 0.040 or 0.045 inches in diameter. Although theillustrated electrode configuration and associated text describe onepreferred method for forming a sensor, a variety of known sensorconfigurations can be employed with the analyte sensor system of thepreferred embodiments, such as U.S. Pat. No. 5,711,861, U.S. Pat. No.6,642,015, U.S. Pat. No. 6,654,625, U.S. Pat. No. 6,565,509, U.S. Pat.No. 6,514,718, U.S. Pat. No. 6,465,066, U.S. Pat. No. 6,214,185, U.S.Pat. No. 5,310,469, U.S. Pat. No. 5,683,562, U.S. Pat. No. 6,579,690,U.S. Pat. No. 6,484,046, U.S. Pat. No. 6,512,939, U.S. Pat. No.6,424,847, and U.S. Pat. No. 6,424,847, for example. Each of the abovepatents is incorporated in its entirety herein by reference. The abovepatents are not inclusive of all applicable analyte sensors; in general,it should be understood that the disclosed embodiments are applicable toa variety of analyte sensor configurations. It is noted that much of thedescription of the preferred embodiments, for example the membranesystem described below, can be implemented not only with in vivosensors, but also with in vitro sensors, such as blood glucose meters(SMBG).

In some embodiments, the working electrode comprises a wire formed froma conductive material, such as platinum, platinum-iridium, palladium,graphite, gold, carbon, conductive polymer, alloys, and the like.Although the electrodes can by formed by a variety of manufacturingtechniques (bulk metal processing, deposition of metal onto a substrate,and the like), it can be advantageous to form the electrodes from platedwire (e.g. platinum on steel wire) or bulk metal (e.g. platinum wire).It is believed that electrodes formed from bulk metal wire providesuperior performance (e.g. in contrast to deposited electrodes),including increased stability of assay, simplified manufacturability,resistance to contamination (e.g. which can be introduced in depositionprocesses), and improved surface reaction (e.g. due to purity ofmaterial) without peeling or delamination.

In some embodiments, the working electrode is formed of platinum-iridiumor iridium wire. In general, platinum-iridium and iridium materials aregenerally stronger (e.g., more resilient and less likely to fail due tostress or strain fracture or fatigue). It is believed thatplatinum-iridium and/or iridium materials can facilitate a wire with asmaller diameter to further decrease the maximum diameter (size) of thesensor (e.g., in vivo portion). Advantageously, a smaller sensordiameter both reduces the risk of clot or thrombus formation (or otherforeign body response) and allows the use of smaller catheters.

The electroactive window 343 of the working electrode 344 is configuredto measure the concentration of an analyte. In an enzymaticelectrochemical sensor for detecting glucose, for example, the workingelectrode measures the hydrogen peroxide produced by an enzyme catalyzedreaction of the analyte being detected and creates a measurableelectronic current For example, in the detection of glucose whereinglucose oxidase produces hydrogen peroxide as a byproduct, hydrogenperoxide reacts with the surface of the working electrode producing twoprotons (2H⁺), two electrons (2e⁻) and one molecule of oxygen (O₂),which produces the electronic current being detected.

In preferred embodiments, the working electrode 344 is covered with aninsulating material 345, for example, a non-conductive polymer.Dip-coating, spray-coating, vapor-deposition, or other coating ordeposition techniques can be used to deposit the insulating material onthe working electrode. In one embodiment, the insulating materialcomprises parylene, which can be an advantageous polymer coating for itsstrength, lubricity, and electrical insulation properties. Generally,parylene is produced by vapor deposition and polymerization ofpara-xylylene (or its substituted derivatives). While not wishing to bebound by theory, it is believed that the lubricious (e.g., smooth)coating (e.g., parylene) on the sensors of some embodiments contributesto minimal trauma and extended sensor life. While parylene coatings aregenerally preferred in some embodiments, any suitable insulatingmaterial can be used, for example, fluorinated polymers,polyethyleneterephthalate, polyurethane, polyimide, other nonconductingpolymers, and the like. Glass or ceramic materials can also be employed.Other materials suitable for use include surface energy modified coatingsystems such as are marketed under the trade names AMC18, AMC148,AMC141, and AMC321 by Advanced Materials Components Express ofBellafonte, Pa. In some alternative embodiments, however, the workingelectrode may not require a coating of insulator.

The reference electrode 346, which can function as a reference electrodealone, or as a dual reference and counter electrode, is formed fromsilver, silver/silver chloride, and the like. In some embodiments, thereference electrode 346 is juxtapositioned and/or twisted with or aroundthe working electrode 344; however other configurations are alsopossible (e.g. coiled within the fluid connector/hub 18 or within afluid coupler 20 or an intradermal or on-skin reference electrode). Inthe illustrated embodiments, the reference electrode 346 is helicallywound around the working electrode 344. The assembly of wires is thenoptionally coated or adhered together with an insulating material,similar to that described above, so as to provide an insulatingattachment.

In some embodiments, a silver wire is formed onto the sensor asdescribed above, and subsequently chloridized to form silver/silverchloride reference electrode. Advantageously, chloridizing the silverwire as described herein enables the manufacture of a referenceelectrode with optimal in vivo performance. Namely, by controlling thequantity and amount of chloridization of the silver to formsilver/silver chloride, improved break-in time, stability of thereference electrode and extended life has been shown with someembodiments. Additionally, use of silver chloride as described aboveallows for relatively inexpensive and simple manufacture of thereference electrode.

In embodiments wherein an outer insulator is disposed, a portion of thecoated assembly structure can be stripped or otherwise removed, forexample, by hand, excimer lasing, chemical etching, laser ablation,grit-blasting (e.g., with sodium bicarbonate or other suitable grit),and the like, to expose the electroactive surfaces. Alternatively, aportion of the electrode can be masked prior to depositing the insulatorin order to maintain an exposed electroactive surface area. In oneexemplary embodiment, grit blasting is implemented to expose theelectroactive surfaces, preferably utilizing a grit material that issufficiently hard to ablate the polymer material, while beingsufficiently soft so as to minimize or avoid damage to the underlyingmetal electrode (e.g., a platinum electrode). Although a variety of“grit” materials can be used (e.g., sand, talc, walnut shell, groundplastic, sea salt, and the like), in some preferred embodiments, sodiumbicarbonate is an advantageous grit-material because it is sufficientlyhard to ablate, e.g. a parylene coating, without damaging, e.g. anunderlying platinum conductor. One additional advantage of sodiumbicarbonate blasting includes its polishing action on the metal as itstrips the polymer layer, thereby eliminating a cleaning step that mightotherwise be necessary.

In the embodiment illustrated in FIG. 3B, a radial window 343 is formedthrough the insulating material 345 to expose a circumferentialelectroactive surface of the working electrode. Additionally, sectionsof electroactive surface of the reference electrode are exposed. Forexample, the sections of electroactive surface can be masked duringdeposition of an outer insulating layer or etched after deposition of anouter insulating layer.

In some applications, cellular attack or migration of cells to thesensor can cause reduced sensitivity and/or function of the device,particularly after the first day of implantation. However, when theexposed electroactive surface is distributed circumferentially about thesensor (e.g. as in a radial window), the available surface area forreaction can be sufficiently distributed so as to minimize the effect oflocal cellular invasion of the sensor on the sensor signal.Alternatively, a tangential exposed electroactive window can be formed,for example, by stripping only one side of the coated assemblystructure. In other alternative embodiments, the window can be providedat the tip of the coated assembly structure such that the electroactivesurfaces are exposed at the tip of the sensor. Other methods andconfigurations for exposing electroactive surfaces can also be employed.

In some embodiments, the working electrode has a diameter of from about0.001 inches or less to about 0.010 inches or more, preferably fromabout 0.002 inches to about 0.008 inches, and more preferably from about0.004 inches to about 0.005 inches. The length of the window can be fromabout 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.078inches) or more, and preferably from about 0.25 mm (about 0.01 inches)to about 0.375 mm (about 0.015 inches). In such embodiments, the exposedsurface area of the working electrode is preferably from about 0.000013in² (0.0000839 cm²) or less to about 0.0025 in² (0.016129 cm²) or more(assuming a diameter of from about 0.001 inches to about 0.010 inchesand a length of from about 0.004 inches to about 0.078 inches). Thepreferred exposed surface area of the working electrode is selected toproduce an analyte signal with a current in the picoAmp range, such asis described in more detail elsewhere herein. However, a current in thepicoAmp range can be dependent upon a variety of factors, for examplethe electronic circuitry design (e.g. sample rate, current draw, A/Dconverter bit resolution, etc.), the membrane system (e.g. permeabilityof the analyte through the membrane system), and the exposed surfacearea of the working electrode. Accordingly, the exposed electroactiveworking electrode surface area can be selected to have a value greaterthan or less than the above-described ranges taking into considerationalterations in the membrane system and/or electronic circuitry. Inpreferred embodiments of a glucose sensor, it can be advantageous tominimize the surface area of the working electrode while maximizing thediffusivity of glucose in order to optimize the signal-to-noise ratiowhile maintaining sensor performance in both high and low glucoseconcentration ranges.

In some alternative embodiments, the exposed surface area of the working(and/or other) electrode can be increased by altering the cross-sectionof the electrode itself. For example, in some embodiments thecross-section of the working electrode can be defined by a cross, star,cloverleaf, ribbed, dimpled, ridged, irregular, or other non-circularconfiguration; thus, for any predetermined length of electrode, aspecific increased surface area can be achieved (as compared to the areaachieved by a circular cross-section). Increasing the surface area ofthe working electrode can be advantageous in providing an increasedsignal responsive to the analyte concentration, which in turn can behelpful in improving the signal-to-noise ratio, for example.

In some alternative embodiments, additional electrodes can be includedwithin the assembly, for example, a three-electrode system (working,reference, and counter electrodes) and/or an additional workingelectrode (e.g. an electrode which can be used to generate oxygen, whichis configured as a baseline subtracting electrode, or which isconfigured for measuring additional analytes). U.S. Patent PublicationNo. US-2005-0161346-A1, U.S. Patent Publication No. US-2005-0143635-A1,and U.S. Patent Publication No. US-2007-0027385-A1 describe some systemsand methods for implementing and using additional working, counter,and/or reference electrodes. In one implementation wherein the sensorcomprises two working electrodes, the two working electrodes arejuxtapositioned (e.g., extend parallel to each other), around which thereference electrode is disposed (e.g., helically wound). In someembodiments wherein two or more working electrodes are provided, theworking electrodes can be formed in a double-, triple-, quad-, etc.helix configuration along the length of the sensor (for example,surrounding a reference electrode, insulated rod, or other supportstructure). The resulting electrode system can be configured with anappropriate membrane system, wherein the first working electrode isconfigured to measure a first signal including glucose and baseline(e.g., background noise) and the additional working electrode isconfigured to measure a baseline signal consisting of baseline only(e.g., configured to be substantially similar to the first workingelectrode without an enzyme disposed thereon). In this way, the baselinesignal can be subtracted from the first signal to produce a glucose-onlysignal that is substantially not subject to fluctuations in the baselineand/or interfering species on the signal.

Although the embodiments of FIGS. 3A to 3C illustrate one electrodeconfiguration including one bulk metal wire helically wound aroundanother bulk metal wire, other electrode configurations are alsocontemplated. In an alternative embodiment, the working electrodecomprises a tube with a reference electrode disposed or coiled inside,including an insulator therebetween. Alternatively, the referenceelectrode comprises a tube with a working electrode disposed or coiledinside, including an insulator therebetween. In another alternativeembodiment, a polymer (e.g., insulating) rod is provided, wherein theelectrodes are deposited (e.g., electro-plated) thereon. In yet anotheralternative embodiment, a metallic (e.g., steel) rod is provided, coatedwith an insulating material, onto which the working and referenceelectrodes are deposited. In yet another alternative embodiment, one ormore working electrodes are helically wound around a referenceelectrode.

Preferably, the electrodes and membrane systems of the preferredembodiments are coaxially formed, namely, the electrodes and/or membranesystem all share the same central axle. While not wishing to be bound bytheory, it is believed that a coaxial design of the sensor enables asymmetrical design without a preferred bend radius. Namely, in contrastto prior art sensors comprising a substantially planar configurationthat can suffer from regular bending about the plane of the sensor, thecoaxial design of the preferred embodiments do not have a preferred bendradius and therefore are not subject to regular bending about aparticular plane (which can cause fatigue failures and the like).However, non-coaxial sensors can be implemented with the sensor systemof the preferred embodiments.

In addition to the above-described advantages, the coaxial sensor designof the preferred embodiments enables the diameter of the connecting endof the sensor (proximal portion) to be substantially the same as that ofthe sensing end (distal portion) such that the protective slotted sheathis able to insert the sensor into the catheter and subsequently slideback over the sensor and release the sensor from the protective slottedsheath, without complex multi-component designs.

In one such alternative embodiment, the two wires of the sensor are heldapart and configured for insertion into the catheter in proximal butseparate locations. The separation of the working and referenceelectrodes in such an embodiment can provide additional electrochemicalstability with simplified manufacture and electrical connectivity. Oneskilled in the art will appreciate that a variety of electrodeconfigurations can be implemented with the preferred embodiments.

In addition to the above-described configurations, the referenceelectrode can be separated from the working electrode, and coiled withina portion of the fluid connector, in some embodiments. In anotherembodiment, the reference electrode is coiled within the fluid connectorand adjacent to its first side. In an alternative embodiment, thereference electrode is coiled within the fluid connector and adjacent toits second side. In such embodiments, the reference electrode is incontact with fluid, such as saline from a saline drip that is flowinginto the host, or such as blood that is being withdrawn from the host.While not wishing to be bound by theory, this configuration is believedto be advantageous because the sensor is thinner, allowing the use ofsmaller catheters and/or a reduced likelihood to thrombus production.

In another embodiment, the reference electrode 346 can be disposedfarther away from the electroactive portion of the working electrode 343(e.g., closer to the fluid connector). In some embodiments, thereference electrode is located proximal to or within the fluid coupler,such as but not limited to, coiled about the catheter adjacent to thefluid coupler or coiled within the fluid coupler and in contact withfluid flowing through the fluid coupler, such as saline. Theseconfigurations can also minimize at least a portion of the sensordiameter and thereby allow the use of smaller catheters and reduce therisk of clots.

In addition to the embodiments described above, the sensor can beconfigured with additional working electrodes as described in U.S.Patent Publication No. US-2005-0143635-A1, U.S. Pat. No. 7,081,195, andU.S. Patent Publication No. US-2007-0027385-A1, herein incorporated byreference in their entirety. For example, in one embodiment have anauxiliary working electrode, wherein the auxiliary working electrodecomprises a wire formed from a conductive material, such as describedwith reference to the glucose-measuring working electrode above.Preferably, the reference electrode, which can function as a referenceelectrode alone, or as a dual reference and counter electrode, is formedfrom silver, Silver/Silver chloride, and the like.

In some embodiments, the electrodes are juxtapositioned and/or twistedwith or around each other; however other configurations are alsopossible. In one example, the auxiliary working electrode and referenceelectrode can be helically wound around the glucose-measuring workingelectrode. Alternatively, the auxiliary working electrode and referenceelectrode can be formed as a double helix around a length of theglucose-measuring working electrode. The assembly of wires can then beoptionally coated together with an insulating material, similar to thatdescribed above, in order to provide an insulating attachment. Someportion of the coated assembly structure is then stripped, for exampleusing an excimer laser, chemical etching, and the like, to expose thenecessary electroactive surfaces. In some alternative embodiments,additional electrodes can be included within the assembly, for example,a three-electrode system (including separate reference and counterelectrodes) as is appreciated by one skilled in the art.

In some alternative embodiments, the sensor is configured as adual-electrode system (e.g., FIGS. 2M-2O, 2Q-2S, and 3D-3I) configuredand arranged to detect two analyte and/or configured as plus-enzyme andminus-enzyme electrodes, as described herein. In one such dual-electrodesystem, a first electrode functions as a hydrogen peroxide sensorincluding a membrane system containing glucose-oxidase disposed thereon,which operates as described herein. A second electrode is a hydrogenperoxide sensor that is configured similar to the first electrode, butwith a modified membrane system (without active enzyme, for example).This second electrode provides a signal composed mostly of the baselinesignal, b.

In some dual-electrode systems, the baseline signal is (electronicallyor digitally) subtracted from the glucose signal to obtain a glucosesignal substantially without baseline. Accordingly, calibration of theresultant difference signal can be performed by solving the equationy=mx with a single paired measurement. Calibration of the insertedsensor in this alternative embodiment can be made less dependent on thevalues/range of the paired measurements, less sensitive to error inmanual blood glucose measurements, and can facilitate the sensor's useas a primary source of glucose information for the user. U.S. PatentPublication No. US-2005-0143635-A1, U.S. Patent Publication No.US-2007-0027385-A1, U.S. Patent Publication No. US-2007-0213611-A1, andU.S. Patent Publication No. US-2008-0083617-A1 each describe systems andmethods for subtracting the baseline from a sensor signal, each of whichis incorporated herein by reference in its entirety.

In some alternative dual-electrode system embodiments, the analytesensor is configured to transmit signals obtained from each electrodeseparately (e.g. without subtraction of the baseline signal). In thisway, the receiver can process these signals to determine additionalinformation about the sensor and/or analyte concentration. For example,by comparing the signals from the first and second electrodes, changesin baseline and/or sensitivity can be detected and/or measured and usedto update calibration (e.g. without the use of a reference analytevalue). In one such example, by monitoring the corresponding first andsecond signals over time, an amount of signal contributed by baselinecan be measured. In another such example, by comparing fluctuations inthe correlating signals over time, changes in sensitivity can bedetected and/or measured.

In some embodiments, the reference electrode can be disposed remotelyfrom the working electrode. In one embodiment, the reference electroderemains within the fluid flow, but is disposed within the fluid coupler.For example, the reference electrode can be coiled within the fluidcoupler such that it is contact with saline flowing into the host, butit is not in physical contact with the host's blood (except when bloodis withdrawn from the catheter). In another embodiment, the referenceelectrode is removed from fluid flow, but still maintains bodily fluidcontact. For example, the reference electrode can be wired to anadhesive patch that is adhered to the host, such that the referenceelectrode is in contact with the host's skin. In yet another embodiment,the reference electrode can be external from the system, such as but notlimited to in contact with the exterior of the ex vivo portion of thesystem, in fluid or electrical contact with a connected saline drip orother medical device, or in bodily contact, such as is generally donewith EKG electrical contacts. While not wishing to be bound by theory,it is believed to locating the reference electrode remotely from theworking electrode permits manufacture of a smaller sensor footprint(e.g., diameter) that will have relatively less affect on the host'sblood flow, such as less thrombosis, than a sensor having a relativelylarger footprint (e.g., wherein both the working electrode and thereference electrode are adjacent to each other and within the bloodpath).

In some embodiments of the sensor system, in vivo portion of the sensor(e.g., the tip 14 a) has an enlarged area (e.g., a bulbous, nailhead-shaped, football-shaped, cone-shaped, cylindrical, etc. portion) ascompared a substantial portion of the sensor (e.g., diameter of the invivo portion of the sensor). The sensor tip can be made bulbous by anyconvenient systems and methods known in the art, such as but not limitedto arc welding, crimping, smashing, welding, molding, heating, andplasma arc welding. While not wishing to be bound by theory, it isbelieved that an enlarged sensor tip (e.g., bulbous) will prevent vesselpiercing as the sensor is pushed forward into the vessel.

The sensor of the preferred embodiments is designed with a minimallyinvasive architecture so as to minimize reactions or effects on theblood flow (or on the sensor in the blood flow). Accordingly, the sensordesigns described herein, consider minimization of dimensions andarrangement of the electrodes and other components of the sensor system,particularly the in vivo portion of the sensor (or any portion of thesensor in fluid contact with the blood flow).

Accordingly, in some embodiments, a substantial portion of the in vivoportion of the sensor is designed with at least one dimension less thanabout 0.020, 0.015, 0.012, 0.010, 0.008, 0.006, 0.005, 0.004 inches. Insome embodiments, a substantial portion of the sensor that is in fluidcontact with the blood flow is designed with at least one dimension lessthan about 0.015, 0.012, 0.010, 0.008, 0.006, 0.005, 0.004, 0.003,0.002, 0.001 inches. As one exemplary embodiment, a sensor such asdescribed in more detail with reference to FIGS. 1A to 1C is formed froma 0.004 inch conductive wire (e.g., platinum) for a diameter of about0.004 inches along a substantial portion of the sensor (e.g., in vivoportion or fluid contact portion). As another exemplary embodiment, asensor such as described in more detail with reference to FIGS. 1A to 1Cis formed from a 0.004 inch conductive wire and vapor deposited with aninsulator material for a diameter of about 0.005 inches along asubstantial portion of the sensor (e.g., in vivo portion or fluidcontact portion), after which a desired electroactive surface area canbe exposed. In the above two exemplary embodiments, the referenceelectrode can be located remote from the working electrode (e.g., formedfrom the conductive wire). While the devices and methods describedherein are directed to use within the host's blood stream, one skilledin the art will recognize that the systems, configurations, methods andprinciples of operation described herein can be incorporated into otheranalyte sensing devices, such as but not limited to subcutaneous devicesor wholly implantable devices such as described in U.S. PatentPublication No. US-2006-0016700-A1, which is incorporated herein byreference in its entirety.

FIG. 3C is a cross section of the sensor shown in FIG. 3B, taken at lineC-C. Preferably, a membrane system (see FIG. 3C) is deposited over theelectroactive surfaces of the sensor and includes a plurality of domainsor layers, such as described in more detail below, with reference toFIGS. 3B and 3C. The membrane system can be deposited on the exposedelectroactive surfaces using known thin film techniques (for example,spraying, electro-depositing, dipping, and the like). In one exemplaryembodiment, each domain is deposited by dipping the sensor into asolution and drawing out the sensor at a speed that provides theappropriate domain thickness. In general, the membrane system can bedisposed over (deposited on) the electroactive surfaces using methodsappreciated by one skilled in the art.

In general, the membrane system includes a plurality of domains, forexample, an electrode domain 347, an interference domain 348, an enzymedomain 349 (for example, including glucose oxidase), and a resistancedomain 350, as shown in FIG. 3C, and can include a high oxygensolubility domain, and/or a bioprotective domain (not shown), such as isdescribed in more detail in U.S. Patent Publication No.US-2005-0245799-A1, and such as is described in more detail below. Themembrane system can be deposited on the exposed electroactive surfacesusing known thin film techniques (for example, vapor deposition,spraying, electro-depositing, dipping, and the like). In alternativeembodiments, however, other vapor deposition processes (e.g., physicaland/or chemical vapor deposition processes) can be useful for providingone or more of the insulating and/or membrane layers, includingultrasonic vapor deposition, electrostatic deposition, evaporativedeposition, deposition by sputtering, pulsed laser deposition, highvelocity oxygen fuel deposition, thermal evaporator deposition, electronbeam evaporator deposition, deposition by reactive sputtering molecularbeam epitaxy, atmospheric pressure chemical vapor deposition (CVD),atomic layer CVD, hot wire CVD, low-pressure CVD, microwaveplasma-assisted CVD, plasma-enhanced CVD, rapid thermal CVD, remoteplasma-enhanced CVD, and ultra-high vacuum CVD, for example. However,the membrane system can be disposed over (or deposited on) theelectroactive surfaces using any known method, as will be appreciated byone skilled in the art.

In some embodiments, one or more domains of the membrane systems areformed from materials such as described above in connection with theporous layer, such as silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyurethanes, cellulosic polymers, polysulfones andblock copolymers thereof including, for example, di-block, tri-block,alternating, random and graft copolymers. U.S. Patent Publication No.US-2005-0245799-A1 describes biointerface and membrane systemconfigurations and materials that may be applied to the preferredembodiments.

Electrode Domain

In selected embodiments, the membrane system comprises an electrodedomain. The electrode domain 347 is provided to ensure that anelectrochemical reaction occurs between the electroactive surfaces ofthe working electrode and the reference electrode, and thus theelectrode domain 347 is preferably situated more proximal to theelectroactive surfaces than the interference and/or enzyme domain.Preferably, the electrode domain includes a coating that maintains alayer of water at the electrochemically reactive surfaces of the sensor.In other words, the electrode domain is present to provide anenvironment between the surfaces of the working electrode and thereference electrode, which facilitates an electrochemical reactionbetween the electrodes. For example, a humectant in a binder materialcan be employed as an electrode domain; this allows for the fulltransport of ions in the aqueous environment. The electrode domain canalso assist in stabilizing the operation of the sensor by acceleratingelectrode start-up and drifting problems caused by inadequateelectrolyte. The material that forms the electrode domain can alsoprovide an environment that protects against pH-mediated damage that canresult from the formation of a large pH gradient due to theelectrochemical activity of the electrodes.

In one embodiment, the electrode domain 347 includes a flexible,water-swellable, hydrogel film having a “dry film” thickness of fromabout 0.05 microns or less to about 20 microns or more, more preferablyfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably stillfrom about 3, 2.5, 2, or 1 microns, or less, to about 3.5, 4, 4.5, or 5microns or more. “Dry film” thickness refers to the thickness of a curedfilm cast from a coating formulation by standard coating techniques.

In certain embodiments, the electrode domain 347 is formed of a curablemixture of a urethane polymer and a hydrophilic polymer. Particularlypreferred coatings are formed of a polyurethane polymer havingcarboxylate or hydroxyl functional groups and non-ionic hydrophilicpolyether segments, wherein the polyurethane polymer is crosslinked witha water-soluble carbodiimide (e.g.1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence ofpolyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

In some preferred embodiments, the electrode domain 347 is formed from ahydrophilic polymer (e.g., a polyamide, a polylactone, a polyimide, apolylactam, a functionalized polyamide, a functionalized polylactone, afunctionalized polyimide, a functionalized polylactam or a combinationthereof) that renders the electrode domain substantially morehydrophilic than an overlying domain, (e.g., interference domain, enzymedomain). In some embodiments, the electrode domain is formedsubstantially entirely and/or primarily from a hydrophilic polymer. Insome embodiments, the electrode domain is formed substantially entirelyfrom PVP. In some embodiments, the electrode domain is formed entirelyfrom a hydrophilic polymer. Useful hydrophilic polymers include but arenot limited to poly-N-vinylpyrrolidone (PVP), poly-N-vinyl-2-piperidone,poly-N-vinyl-2-caprolactam, poly-N-vinyl-3-methyl-2-caprolactam,poly-N-vinyl-3-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-piperidone,poly-N-vinyl-4-methyl-2-caprolactam, poly-N-vinyl-3-ethyl-2-pyrrolidone,poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole,poly-N,N-dimethylacrylamide, polyvinyl alcohol, polyacrylic acid,polyethylene oxide, poly-2-ethyl-oxazoline, copolymers thereof andmixtures thereof. A blend of two or more hydrophilic polymers ispreferred in some embodiments. In some preferred embodiments, thehydrophilic polymer(s) is not crosslinked. In alternative embodiments,crosslinking is preferred, such as by adding a crosslinking agent, suchas but not limited to EDC, or by irradiation at a wavelength sufficientto promote crosslinking between the hydrophilic polymer molecules, whichis believed to create a more tortuous diffusion path through the domain.

An electrode domain formed from a hydrophilic polymer (e.g. PVP) hasbeen shown to substantially reduce break-in time of analyte sensors; forexample, a glucose sensor utilizing a cellulosic-based interferencedomain such as described in more detail elsewhere herein. In someembodiments, a uni-component electrode domain formed from a singlehydrophilic polymer (e.g. PVP) has been shown to substantially reducebreak-in time of a glucose sensor to less than about 2 hours, less thanabout 1 hour, less than about 20 minutes and/or substantiallyimmediately, such as exemplified in Examples 9 through 11 and 13.Generally, sensor break-in is the amount of time required (afterimplantation) for the sensor signal to become substantiallyrepresentative of the analyte concentration. Sensor break-in includesboth membrane break-in and electrochemical break-in, which are describedin more detail elsewhere herein. In some embodiments, break-in time isless than about 2 hours. In other embodiments, break-in time is lessthan about 1 hour. In still other embodiments, break-in time is lessthan about 30 minutes, less than about 20 minutes, less than about 15minutes, less than about 10 minutes, or less. In a preferred embodiment,sensor break-in occurs substantially immediately. Advantageously, inembodiments wherein the break-in time is about 0 minutes (substantiallyimmediately), the sensor can be inserted and begin providingsubstantially accurate analyte (e.g. glucose) concentrations almostimmediately post-insertion, for example, wherein membrane break-in doesnot limit start-up time.

While not wishing to be bound by theory, it is believed that providingan electrode domain that is substantially more hydrophilic than the nextmore distal membrane layer or domain (e.g. the overlaying domain; thelayer more distal to the electroactive surface than the electrodedomain, such as an interference domain or an enzyme domain) reduces thebreak-in time of an implanted sensor, by increasing the rate at whichthe membrane system is hydrated by the surrounding host tissue. Whilenot wishing to be bound by theory, it is believed that, in general,increasing the amount of hydrophilicity of the electrode domain relativeto the overlaying layer (e.g. the distal layer in contact with electrodedomain, such as the interference domain, enzyme domain, etc.), increasesthe rate of water absorption, resulting in reduced sensor break-in time.The hydrophilicity of the electrode domain can be substantiallyincreased by the proper selection of hydrophilic polymers, based ontheir hydrophilicity relative to each other and relative to theoverlaying layer (e.g. cellulosic-based interference domain), withpreferred polymers being substantially more hydrophilic than theoverlaying layer. In one exemplary embodiment, PVP forms the electrodedomain, the interference domain is formed from a blend of cellulosicderivatives, such as but not limited to cellulose acetate butyrate andcellulose acetate; it is believed that since PVP is substantially morehydrophilic than the cellulosic-based interference domain, the PVPrapidly draws water into the membrane to the electrode domain, andenables the sensor to function with a desired sensitivity and accuracyand starting within a substantially reduced time period afterimplantation. Reductions in sensor break-in time reduce the amount oftime a host must wait to obtain sensor readings, which is particularlyadvantageous not only in ambulatory applications, but particularly inhospital settings where time is critical.

While not wishing to be bound by theory, it is believed that when thewater absorption of the overlying domain (e.g. the domain overlying theelectrode domain) is less than the water absorption of the electrodedomain (e.g. during membrane equilibration), then the difference inwater absorption between the two domains will drive membraneequilibration and thus membrane break-in. Namely, increasing thedifference in hydrophilicity (e.g. between the two domains) results inan increase in the rate of water absorption, which, in turn, results ina decrease in membrane break-in time and/or sensor break-in time. Asdiscussed elsewhere herein, the relative hydrophilicity of the electrodedomain as compared to the overlying domain can be modulated by aselection of more hydrophilic materials for formation of the electrodedomain (and/or more hydrophobic materials for the overlying domain(s)).For example, an electrode domain with hydrophilic polymer capable ofabsorbing larger amounts of water can be selected instead of a secondhydrophilic polymer that is capable of absorbing less water than thefirst hydrophilic polymer. In some embodiments, the water contentdifference between the electrode domain and the overlying domain (e.g.during or after membrane equilibration) is from about 1% or less toabout 90% or more. In other embodiments, the water content differencebetween the electrode domain and the overlying domain is from about 10%or less to about 80% or more. In still other embodiments, the watercontent difference between the electrode domain and the overlying domainis from about 30% or less to about 60% or more. In preferredembodiments, the electrode domain absorbs 5 wt. % or less to 95 wt. % ormore water, preferably 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 wt. % toabout 55, 60, 65, 70, 75, 80, 85, 90 or 95 wt. % water than the adjacent(overlying) domain (e.g. the domain that is more distal to theelectroactive surface than the electrode domain).

In another example, the rate of water absorption by a polymer can beaffected by other factors, such as but not limited to the polymer'smolecular weight. For example, the rate of water absorption by PVP isdependent upon its molecular weight, which is typically from about 40kDa or less to about 360 kDa or more; with a lower molecular weight PVP(e.g. 40 kDa) absorbing water faster than a higher molecular weight PVP.Accordingly, modulating factors, such as molecular weight, that affectthe rate of water absorption by a polymer, can promote the properselection of materials for electrode domain fabrication. In oneembodiment, a lower molecular weight PVP is selected, to reduce break-intime.

Preferably, the electrode domain is deposited by known thin filmdeposition techniques (e.g. spray coating or dip-coating theelectroactive surfaces of the sensor). In some embodiments, theelectrode domain is formed by dip-coating the electroactive surfaces inan electrode domain solution (e.g., 5, 10, 15, 20, 25 or 30% or more PVPin deionized water) and curing the domain for a time of from about 15minutes to about 30 minutes at a temperature of from about 40° C. toabout 55° C. (and can be accomplished under vacuum (e.g., 20 to 30mmHg)). In embodiments wherein dip-coating is used to deposit theelectrode domain, a preferred insertion rate of from about 1 to about 3inches per minute into the electrode domain solution, with a preferreddwell time of from about 0.5 to about 2 minutes in the electrode domainsolution, and a preferred withdrawal rate of from about 0.25 to about 2inches per minute from the electrode domain solution provide afunctional coating. However, values outside of those set forth above canbe acceptable or even desirable in certain embodiments, for example,depending upon solution viscosity and solution surface tension, as isappreciated by one skilled in the art. In one embodiment, theelectroactive surfaces of the electrode system are dip-coated one time(one layer) and cured at 50° C. under vacuum for 20 minutes. In anotherembodiment, the electroactive surfaces of the electrode system isdip-coated and cured at 50° C. under vacuum for 20 minutes a first time,followed by dip coating and curing at 50° C. under vacuum for 20 minutesa second time (two layers). In still other embodiments, theelectroactive surfaces can be dip-coated three or more times (three ormore layers). In other embodiments, the 1, 2, 3 or more layers of PVPare applied to the electroactive surfaces by spray coating or vapordeposition. In some embodiments, a crosslinking agent (e.g. EDC) can beadded to the electrode domain casting solution to promote crosslinkingwithin the domain (e.g. between electrode domain polymer components,latex, etc.). In some alternative embodiments however, no crosslinkingagent is used and the electrode domain is not substantially crosslinked.

In some embodiments, the deposited PVP electrode domain 347 has a “dryfilm” thickness of from about 0.05 microns or less to about 20 micronsor more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3,0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, andmore preferably still from about 2, 2.5 or 3 microns to about 3.5, 4,4.5, or 5 microns.

Although an independent electrode domain 347 is described herein, insome embodiments sufficient hydrophilicity can be provided in theinterference domain and/or enzyme domain (the domain adjacent to theelectroactive surfaces) so as to provide for the full transport of ionsin the aqueous environment (e.g. without a distinct electrode domain).In these embodiments, an electrode domain is not necessary.

Interference Domain

Interferents are molecules or other species that are reduced or oxidizedat the electrochemically reactive surfaces of the sensor, eitherdirectly or via an electron transfer agent, to produce a false positiveanalyte signal (e.g., a non-analyte-related signal). This false positivesignal causes the host's analyte concentration (e.g., glucoseconcentration) to appear higher than the true analyte concentration.False-positive signal is a clinically significant problem in someconventional sensors. For example in a case of a dangerouslyhypoglycemic situation, wherein the host has ingested an interferent(e.g., acetaminophen), the artificially high glucose signal can lead thehost to believe that he is euglycemic (or, in some cases,hyperglycemic). As a result, the host can make inappropriate treatmentdecisions, such as taking no action, when the proper course of action isto begin eating. In another example, in the case of a euglycemic orhyperglycemic situation, wherein a host has consumed acetaminophen, anartificially high glucose signal caused by the acetaminophen can leadthe host to believe that his or her glucose concentration is much higherthan it truly is. Again, as a result of the artificially high glucosesignal, the host can make inappropriate treatment decisions, such asgiving himself too much insulin, which in turn can lead to a dangeroushypoglycemic episode.

In preferred embodiments, an interference domain 348 is provided thatsubstantially restricts or blocks the flow of one or more interferingspecies therethrough; thereby substantially preventing artificial signalincreases. Some known interfering species for a glucose sensor, asdescribed in more detail herein, include acetaminophen, ascorbic acid,bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen,L-dopa, methyl dopa, salicylate, tetracycline, tolazamide, tolbutamide,triglycerides, and uric acid. In general, the interference domain of thepreferred embodiments is less permeable to one or more of theinterfering species than to the measured species, e.g. the product of anenzymatic reaction that is measured at the electroactive surface(s),such as but not limited to H₂O₂.

In one embodiment, the interference domain 348 is formed from one ormore cellulosic derivatives. Cellulosic derivatives can include, but arenot limited to, cellulose esters and cellulose ethers. In general,cellulosic derivatives include polymers such as cellulose acetate,cellulose acetate butyrate, 2-hydroxyethyl cellulose, cellulose acetatephthalate, cellulose acetate propionate, cellulose acetate trimellitate,and the like, as well as their copolymers and terpolymers with othercellulosic or non-cellulosic monomers. Cellulose is a polysaccharidepolymer of β-D-glucose. While cellulosic derivatives are generallypreferred, other polymeric polysaccharides having similar properties tocellulosic derivatives can also be employed in the preferredembodiments.

In one preferred embodiment, the interference domain 348 is formed fromcellulose acetate butyrate. Cellulose acetate butyrate with a molecularweight of about 10,000 daltons to about 75,000 daltons, preferably fromabout 15,000, 20,000, or 25,000 daltons to about 50,000, 55,000, 60,000,65,000, or 70,000 daltons, and more preferably about 20,000 daltons isemployed. In certain embodiments, however, higher or lower molecularweights can be preferred. In some embodiments, a blend of two or morecellulose acetate butyrates having different molecular weights ispreferred. While a “blend” as defined herein (a composition of two ormore substances that are not substantially chemically combined with eachother and are capable of being separated) is generally preferred, incertain embodiments a single polymer incorporating differentconstituents (e.g. separate constituents as monomeric units and/orsubstituents on a single polymer chain) can be employed instead.Additionally, a casting solution or dispersion of cellulose acetatebutyrate at a wt. % of from about 5% to about 25%, preferably from about5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% to about 16%, 17%,18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%, and more preferably from about5% to about 15% is preferred. Preferably, the casting solution includesa solvent or solvent system, for example an acetone:ethanol solventsystem. Higher or lower concentrations can be preferred in certainembodiments. In alternative embodiments, a single solvent (e.g. acetone)is used to form a symmetrical membrane domain. A single solvent is usedin casting solutions for forming symmetric membrane layer(s). Aplurality of layers of cellulose acetate butyrate can be advantageouslycombined to form the interference domain in some embodiments, forexample, three layers can be employed. It can be desirable to employ amixture of cellulose acetate butyrate components with differentmolecular weights in a single solution, or to deposit multiple layers ofcellulose acetate butyrate from different solutions comprising celluloseacetate butyrate of different molecular weights, differentconcentrations, and/or different chemistries (e.g. functional groups).It can also be desirable to include additional substances in the castingsolutions or dispersions, e.g. functionalizing agents, crosslinkingagents, other polymeric substances, substances capable of modifying thehydrophilicity/hydrophobicity of the resulting layer, and the like.

In one alternative embodiment, the interference domain 348 is formedfrom cellulose acetate. Cellulose acetate with a molecular weight ofabout 30,000 daltons or less to about 100,000 daltons or more,preferably from about 35,000, 40,000, or 45,000 daltons to about 55,000,60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, or 95,000daltons, and more preferably about 50,000 daltons is preferred. In someembodiments, a blend of two or more cellulose acetates having differentmolecular weights is preferred. Additionally, a casting solution ordispersion of cellulose acetate at a weight percent of about 3% to about10%, preferably from about 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, or 6.5%to about 7.5%, 8.0%, 8.5%, 9.0%, or 9.5%, and more preferably about 8%is preferred. In certain embodiments, however, higher or lower molecularweights and/or cellulose acetate weight percentages can be preferred. Itcan be desirable to employ a mixture of cellulose acetates withmolecular weights in a single solution, or to deposit multiple layers ofcellulose acetate from different solutions comprising cellulose acetatesof different molecular weights, different concentrations, or differentchemistries (e.g. functional groups). It can also be desirable toinclude additional substances in the casting solutions or dispersionssuch as described in more detail above.

In addition to forming an interference domain from only celluloseacetate(s) or only cellulose acetate butyrate(s), the interferencedomain 348 can be formed from combinations or blends of cellulosicderivatives, such as but not limited to cellulose acetate and celluloseacetate butyrate, or combinations of layer(s) of cellulose acetate andlayer(s) of cellulose acetate butyrate. In some embodiments, a blend ofcellulosic derivatives (for formation of an interference domain)includes up to about 10 wt. % or more of cellulose acetate. For example,about 1, 2, 3, 4, 5, 6, 7, 8, 9 wt. % or more cellulose acetate ispreferred, in some embodiments. In some embodiments, the cellulosicderivatives blend includes from about 90 wt. % or less to about 100 wt.% cellulose acetate butyrate. For example, in some embodiments, theblend includes about 91, 92, 93, 94, 95, 96, 97, 98 or 99 wt. %cellulose acetate butyrate. In some embodiments, the cellulosicderivative blend includes from about 1.5, 2.0, 2.5, 3.0 or 3.5 wt. %cellulose acetate to about 98.5, 98.0, 97.5, 97.0 or 96.5 wt. %cellulose acetate butyrate. In other embodiments, the blend includesfrom about 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 wt. % cellulose acetateto about 96, 95.5, 95, 94.5, 94, 93.3, 93, 92.5 or 92 wt. % celluloseacetate butyrate. In still other embodiments, the blend includes fromabout 8.5, 9.0, 9.5, 10.0, 10.5 or 11.0 wt. % cellulose acetate to about91.5, 91.0, 90.5, 90, 89.5 or 89 wt. % cellulose acetate butyrate.

In some embodiments, preferred blends of cellulose acetate and celluloseacetate butyrate contain from about 1.5 parts or less to about 60 partsor more cellulose acetate butyrate to one part of cellulose acetate. Insome embodiments, a blend contains from about 2 parts to about 40 partscellulose acetate butyrate to one part cellulose acetate. In otherembodiments, about 4, 6, 8, 10, 12, 14, 16, 18 or 20 parts celluloseacetate butyrate to one part cellulose acetate is preferred forformation of the interference domain 348. In still other embodiments, ablend having from 22, 24, 26, 28, 30, 32, 34, 36 or 38 parts celluloseacetate butyrate to one part cellulose acetate is preferred. As isdiscussed elsewhere herein, cellulose acetate butyrate is relativelymore hydrophobic than cellulose acetate. Accordingly, the celluloseacetate/cellulose acetate butyrate blend contains substantially morehydrophobic than hydrophilic components.

Cellulose acetate butyrate is a cellulosic polymer having both acetyland butyl groups, in addition to hydroxyl groups. Acetyl groups are morehydrophilic than butyl groups, and hydroxyl groups are more hydrophilicthan both acetyl and butyl groups. Accordingly, the relative amounts ofacetyl, butyl and hydroxyl groups can be used to modulate thehydrophilicity/hydrophobicity of the cellulose acetate butyrate of thecellulose acetate/cellulose acetate butyrate blend. A cellulose acetatebutyrate can be selected based on the compound's relative amounts ofacetate, butyrate and hydroxyl groups; and a cellulose acetate can beselected based on the compounds relative amounts of acetate and hydroxylgroups. For example, in some embodiments, a cellulose acetate butyratehaving about 35% or less acetyl groups, about 10% to about 25% butylgroups, and hydroxyl groups making up the remainder is preferred forformation of the interference domain 348. In other embodiments acellulose acetate butyrate having from about 25% to about 34% acetylgroups and from about 15 to about 20% butyl groups is preferred. Instill other embodiments, the preferred cellulose acetate butyratecontains from about 28% to about 30% acetyl groups and from about 16 toabout 18% butyl groups. In yet another embodiment, the cellulose acetatebutyrate can have no acetate groups and from about 20% to about 60%butyrate groups. In yet another embodiment, the cellulose acetatebutyrate has about 55% butyrate groups and no acetate groups.

While an asymmetric interference domain can be used in some alternativeembodiments, a symmetrical interference domain 348 (e.g., ofcellulosic-derivative blends, such as but not limited to blends ofcellulose acetate components and cellulose acetate butyrate components)is preferred in some embodiments. Symmetrical membranes are uniformthroughout their entire structure, without gradients of pore densitiesor sizes, or a skin on one side but not the other, for example. Invarious embodiments, a symmetrical interference domain 348 can be formedby the appropriate selection of a solvent (e.g. no anti-solvent isused), for making the casting solution. Appropriate solvents includesolvents belonging to the ketone family that are able to solvate thecellulose acetate and cellulose acetate butyrate. The solvents includebut are not limited to acetone, methyl ethyl ketone, methyl n-propylketone, cyclohexanone, and diacetone alcohol. Other solvents, such asfurans (e.g. tetra-hydro-furan and 1,4-dioxane), may be preferred insome embodiments. In one exemplary embodiment, from about 7 wt. % toabout 9 wt. % solids (e.g. a blend of cellulosic derivatives, such ascellulose acetate and cellulose acetate butyrate) are blended with asingle solvent (e.g. acetone), to form the casting solution for asymmetrical interference domain. In another embodiment, from about 10 toabout 15% solids are blended with acetone to form the casting solution.In yet another embodiment, from about 16 to about 18% solids are blendedwith acetone to form the casting solution. A relatively lower or greaterweight percent of solids is preferred to form the casting solution, insome embodiments.

The casting solution can be applied either directly to the electroactivesurface(s) of the sensor or on top of an electrode domain layer (ifincluded in the membrane system). The casting solution can be appliedusing any known thin film technique, as discussed elsewhere herein.Additionally, in various embodiments, a symmetrical interference domain348 includes at least one layer; and in some embodiments, two, three ormore layers are formed by the sequential application and curing of thecasting solution.

The concentration of solids in the casting solution can be adjusted todeposit a sufficient amount of solids on the electrode in one layer(e.g. in one dip or spray) to form a membrane layer with sufficientblocking ability, such that the equivalent glucose signal of aninterferent (e.g. compounds with an oxidation or reduction potentialthat overlaps with that of the measured species (e.g. H₂O₂)), measuredby the sensor, is about 60 mg/dL or less. For example, in someembodiments, the casting solution's percentage of solids is adjustedsuch that only a single layer (e.g. dip one time) is required to deposita sufficient amount of the cellulose acetate/cellulose acetate butyrateblend to form a functional symmetric interference domain thatsubstantially blocks passage therethrough of at least one interferent,such as but not limited to acetaminophen, ascorbic acid, dopamine,ibuprofen, salicylic acid, tolbutamide, tetracycline, creatinine, uricacid, ephedrine, L-dopa, methyl dopa and tolazamide. In someembodiments, the amount of interference domain material deposited by assingle dip is sufficient to reduce the equivalent glucose signal of theinterferant (e.g. measured by the sensor) to about 60 mg/dl or less. Inpreferred embodiments, the interferent's equivalent glucose signalresponse (measured by the sensor) is 50 mg/dl or less. In more preferredembodiments, the interferent produces an equivalent glucose signalresponse of 40 mg/dl or less. In still more preferred embodiments, theinterferent produces an equivalent glucose signal response of less thanabout 30, 20 or 10 mg/dl. In one exemplary embodiment, the interferencedomain is configured to substantially block acetaminophen passagetherethrough, wherein the equivalent glucose signal response of theacetaminophen is less than about 30 mg/dl.

In alternative embodiments, the interference domain 348 is configured tosubstantially block a therapeutic dose of acetaminophen. The term“therapeutic dose” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the quantity of any substance required toeffect the cure of a disease, to relieve pain, or that will correct themanifestations of a deficiency of a particular factor in the diet, suchas the effective dose used with therapeutically applied compounds, suchas drugs. For example, a therapeutic dose of acetaminophen can be anamount of acetaminophen required to relieve headache pain or reduce afever. As a further example, 1,000 mg of acetaminophen taken orally,such as by swallowing two 500 mg tablets of acetaminophen, is thetherapeutic dose frequently taken for headaches. In some embodiments,the interference membrane is configured to block a therapeutic dose ofacetaminophen, wherein the equivalent glucose signal response of theacetaminophen is less than about 60 mg/dl. In a preferred embodiment,the interference membrane is configured to block a therapeutic dose ofacetaminophen, wherein the equivalent glucose signal response of theacetaminophen is less than about 40 mg/dl. In a more preferredembodiment, the interference membrane is configured to block atherapeutic dose of acetaminophen, wherein the equivalent glucose signalresponse of the acetaminophen is less than about 30 mg/dl.

While not wishing to be bound by theory, it is believed that, withrespect to symmetrical cellulosic-based membranes, there is an inverselyproportional balance between interferent blocking and analytesensitivity. Namely, changes to the interference domain configurationthat increase interferent blocking can result in a correspondingdecrease in sensor sensitivity. Sensor sensitivity is discussed in moredetail elsewhere herein. It is believed that the balance betweeninterferent blocking and sensor sensitivity is dependent upon therelative proportions of hydrophobic and hydrophilic components of themembrane layer (e.g. the interference domain), with sensors having morehydrophobic interference domains having increased interferent blockingbut reduces sensitivity; and sensors having more hydrophilicinterference domains having reduced interferent blocking but increasedsensitivity. It is believed that the hydrophobic and hydrophiliccomponents of the interference domain can be balanced, to promote adesired level of interferent blocking while at the same time maintaininga desired level of analyte sensitivity. The interference domainhydrophobe-hydrophile balance can be manipulated and/or maintained bythe proper selection and blending of the hydrophilic and hydrophobicinterference domain components (e.g. cellulosic derivatives havingacetyl, butyryl, propionyl, methoxy, ethoxy, propoxy, hydroxyl,carboxymethyl, and/or carboxyethyl groups). For example, celluloseacetate is relatively more hydrophilic than cellulose acetate butyrate.In some embodiments, increasing the percentage of cellulose acetate (orreducing the percentage of cellulose acetate butyrate) can increase thehydrophilicity of the cellulose acetate/cellulose acetate butyrateblend, which promotes increased permeability to hydrophilic species,such as but not limited to glucose, H₂O₂ and some interferents (e.g.acetaminophen). In another embodiment, the percentage of celluloseacetate butyrate is increased to increase blocking of interferants, butless permeability to some desired molecules, such as H₂O₂ and glucose,is also reduced.

One method, of manipulating the hydrophobe-hydrophile balance of theinterference domain, is to select the appropriate percentages of acetylgroups (relatively more hydrophilic than butyl groups), butyl groups(relatively more hydrophobic than acetyl groups) and hydroxyl groups ofthe cellulose acetate butyrate used to form the interference domain 348.For example, increasing the percentage of acetate groups on thecellulose acetate butyrate will make the cellulose acetate butyrate morehydrophilic. In another example, increasing the percentage of butylgroups on the cellulose acetate butyrate will make the cellulose acetatebutyrate more hydrophobic. In yet another example, increasing thepercentage of hydroxyl groups will increase the hydrophilicity of thecellulose acetate butyrate. Accordingly, the selection of a celluloseacetate butyrate that is more or less hydrophilic (or more or lesshydrophobic) can modulate the over-all hydrophilicity of the celluloseacetate/cellulose acetate butyrate blend. In one exemplary embodiment,an interference domain can be configured to be relatively morehydrophobic (and therefore block interferants more strongly) by reducingthe percentage of acetyl or hydroxyl groups or by increasing thepercentage of butyl groups on the cellulose acetate butyrate used in thecasting solution (while maintaining the relative ratio of celluloseacetate to cellulose acetate butyrate).

In some alternative embodiments, the interference domain 348 is formedof a blend of cellulosic derivatives, wherein the hydrophilic andhydrophobic components of the interference domain are balanced, suchthat the glucose sensitivity is from about 1 pA/mg/dL to about 100pA/mg/dL, and at least one interferent is sufficiently blocked frompassage through the interference domain such that the equivalent glucosesignal response of the at least one interferent is less than about 60mg/dL. In a preferred embodiment, the glucose sensitivity is from about5 pA/mg/dL to about 25 pA/mg/dL. In a more preferred embodiments, theglucose sensitivity is from about 5 pA/mg/dL to about 25 pA/mg/dL andthe equivalent glucose signal response of the at least one interferentis less than about 40 mg/dL. In a still more preferred embodiments, theglucose sensitivity is from about 5 pA/mg/dL to about 25 pA/mg/dL andthe equivalent glucose signal response of the at least one interferentis less than about 30 mg/dL. In some embodiments, the balance betweenhydrophilic and hydrophobic components of the interference domain can beachieved by adjusting the amounts of hydrophilic and hydrophobiccomponents, relative to each other, as well as adjusting the hydrophilicand hydrophobic groups (e.g. acetyl, butyryl, propionyl, methoxy,ethoxy, propoxy, hydroxyl, carboxymethyl, and/or carboxyethyl groups) ofthe components themselves (e.g. cellulosic derivatives, such as but notlimited to cellulose acetate and cellulose acetate butyrate).

In some alternative embodiments, additional polymers, such as NAFION®,can be used in combination with cellulosic derivatives to provideequivalent and/or enhanced function of the interference domain 348. Asone example, a layer of a 5 wt. % NAFION® casting solution was appliedover a previously applied (e.g., and cured) layer of 8 wt. % celluloseacetate, e.g., by dip coating at least one layer of cellulose acetateand subsequently dip coating at least one layer NAFION® onto aneedle-type sensor such as described with reference to the preferredembodiments. Any number of coatings or layers formed in any order may besuitable for forming the interference domain of the preferredembodiments.

In some alternative embodiments, more than one cellulosic derivative canbe used to form the interference domain 348 of the preferredembodiments. In general, the formation of the interference domain on asurface utilizes a solvent or solvent system, in order to solvate thecellulosic derivative(s) (or other polymer) prior to film formationthereon. In preferred embodiments, acetone and ethanol are used assolvents for cellulose acetate; however one skilled in the artappreciates the numerous solvents that are suitable for use withcellulosic derivatives (and other polymers). Additionally, one skilledin the art appreciates that the preferred relative amounts of solventcan be dependent upon the cellulosic derivative (or other polymer) used,its molecular weight, its method for deposition, its desired thickness,and the like. However, a percent solute of from about 1 wt. % to about25 wt. % is preferably used to form the interference domain solution soas to yield an interference domain having the desired properties. Thecellulosic derivative (or other polymer) used, its molecular weight,method for deposition, and desired thickness can be adjusted, dependingupon one or more other of the parameters, and can be varied accordinglyas is appreciated by one skilled in the art.

In some alternative embodiments, other polymer types that can beutilized as a base material for the interference domain 348 includingpolyurethanes, polymers having pendant ionic groups, and polymers havingcontrolled pore size, for example. In one such alternative embodiment,the interference domain includes a thin, hydrophobic membrane that isnon-swellable and restricts diffusion of high molecular weight species.The interference domain 48 is permeable to relatively low molecularweight substances, such as hydrogen peroxide, but restricts the passageof higher molecular weight substances, including glucose and ascorbicacid. Other systems and methods for reducing or eliminating interferencespecies that can be applied to the membrane system of the preferredembodiments are described in U.S. Pat. No. 7,074,307, U.S. PatentPublication No. US-2005-0176136-A1, U.S. Pat. No. 7,081,195, and U.S.Patent Publication No. US-2005-0143635-A1. In some alternativeembodiments, a distinct interference domain is not included.

In some embodiments, the interference domain 348 is deposited eitherdirectly onto the electroactive surfaces of the sensor or onto thedistal surface of the electrode domain, for a domain thickness of fromabout 0.05 micron or less to about 20 microns or more, more preferablyfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably stillfrom about 1, 1.5 or 2 microns to about 2.5 or 3 microns. Thickermembranes can also be desirable in certain embodiments, but thinnermembranes are generally preferred because they have a lower impact onthe rate of diffusion of hydrogen peroxide from the enzyme membrane tothe electrodes

In general, the membrane systems of the preferred embodiments can beformed and/or deposited on the exposed electroactive surfaces (e.g., oneor more of the working and reference electrodes) using known thin filmtechniques (for example, casting, spray coating, drawing down,electro-depositing, dip coating, and the like), however casting or otherknown application techniques can also be utilized. Preferably, theinterference domain 348 is deposited by spray or dip coating. In oneexemplary embodiment of a needle-type (transcutaneous) sensor such asdescribed herein, the interference domain is formed by dip coating thesensor into an interference domain solution using an insertion rate offrom about 0.5 inch/min to about 60 inches/min, preferably 1 inch/min, adwell time of from about 0 minute to about 2 minutes, preferably about 1minute, and a withdrawal rate of from about 0.5 inch/minute to about 60inches/minute, preferably about 1 inch/minute, and curing (drying) thedomain from about 1 minute to about 30 minutes, preferably from about 3minutes to about 15 minutes (and can be accomplished at room temperatureor under vacuum (e.g., 20 to 30 mmHg)). In one exemplary embodimentincluding cellulose acetate butyrate interference domain, a 3-minutecure (i.e., dry) time is preferred between each layer applied. Inanother exemplary embodiment employing a cellulose acetate interferencedomain, a 15 minute cure (i.e., dry) time is preferred between eachlayer applied.

In some embodiments, the dip process can be repeated at least one timeand up to 10 times or more. In other embodiments, only one dip ispreferred. The preferred number of repeated dip processes depends uponthe cellulosic derivative(s) used, their concentration, conditionsduring deposition (e.g., dipping) and the desired thickness (e.g.,sufficient thickness to provide functional blocking of certaininterferents), and the like. In some embodiments, 1 to 3 microns may bepreferred for the interference domain thickness; however, values outsideof these can be acceptable or even desirable in certain embodiments, forexample, depending upon viscosity and surface tension, as is appreciatedby one skilled in the art. In one exemplary embodiment, an interferencedomain is formed from three layers of cellulose acetate butyrate. Inanother exemplary embodiment, an interference domain is formed from 10layers of cellulose acetate. In another embodiment, an interferencedomain is formed from 1 layer of a blend of cellulose acetate andcellulose acetate butyrate. In alternative embodiments, the interferencedomain can be formed using any known method and combination of celluloseacetate and cellulose acetate butyrate, as will be appreciated by oneskilled in the art.

In some embodiments, the electroactive surface can be cleaned prior toapplication of the interference domain 348. In some embodiments, theinterference domain 348 of the preferred embodiments can be useful as abioprotective or biocompatible domain, namely, a domain that interfaceswith host tissue when implanted in an animal (e.g., a human) due to itsstability and biocompatibility.

Enzyme Domain

In preferred embodiments, the membrane system further includes an enzymedomain 349 disposed more distally from the electroactive surfaces thanthe interference domain 348; however other configurations can bedesirable. In the preferred embodiments, the enzyme domain provides anenzyme to catalyze the reaction of the analyte and its co-reactant, asdescribed in more detail below. In the preferred embodiments of aglucose sensor, the enzyme domain includes glucose oxidase; howeverother oxidases, for example, galactose oxidase or uricase oxidase, canalso be used.

For an enzyme-based electrochemical glucose sensor to perform well, thesensor's response is preferably limited by neither enzyme activity norco-reactant concentration. Because enzymes, including glucose oxidase,are subject to deactivation as a function of time even in ambientconditions, this behavior is compensated for in forming the enzymedomain. Preferably, the enzyme domain is constructed of aqueousdispersions of colloidal polyurethane polymers including the enzyme.However, in alternative embodiments the enzyme domain is constructedfrom an oxygen enhancing material, for example, silicone, orfluorocarbon, in order to provide a supply of excess oxygen duringtransient ischemia. Preferably, the enzyme is immobilized within thedomain. See, e.g., U.S. Patent Publication No. US-2005-0054909-A1.

In preferred embodiments, the enzyme domain is deposited onto theinterference domain for a domain thickness of from about 0.05 micron orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. However in some embodiments,the enzyme domain can be deposited directly onto the electroactivesurfaces. Preferably, the enzyme domain is deposited by spray or dipcoating. In one embodiment of needle-type (transcutaneous) sensor suchas described herein, the enzyme domain is formed by dip coating theinterference domain coated sensor into an enzyme domain solution andcuring the domain for from about 15 to about 30 minutes at a temperatureof from about 40° C. to about 55° C. (and can be accomplished undervacuum (e.g. 20 to 30 mmHg)). In embodiments wherein dip coating is usedto deposit the enzyme domain at room temperature, a preferred insertionrate of from about 0.25 inch per minute to about 3 inches per minute,with a preferred dwell time of from about 0.5 minutes to about 2minutes, and a preferred withdrawal rate of from about 0.25 inch perminute to about 2 inches per minute provides a functional coating.However, values outside of those set forth above can be acceptable oreven desirable in certain embodiments, for example, depending uponviscosity and surface tension, as is appreciated by one skilled in theart. In one embodiment, the enzyme domain is formed by dip coating twotimes (namely, forming two layers) in an enzyme domain solution andcuring at 50° C. under vacuum for 20 minutes. However, in someembodiments, the enzyme domain can be formed by dip coating and/or spraycoating one or more layers at a predetermined concentration of thecoating solution, insertion rate, dwell time, withdrawal rate, and/ordesired thickness.

Resistance Domain

In preferred embodiments, the membrane system includes a resistancedomain 350 disposed more distal from the electroactive surfaces than theenzyme domain. Although the following description is directed to aresistance domain for a glucose sensor, the resistance domain can bemodified for other analytes and co-reactants as well.

There exists a molar excess of glucose relative to the amount of oxygenin blood; that is, for every free oxygen molecule in extracellularfluid, there are typically more than 100 glucose molecules present (seeUpdike et al., Diabetes Care 5:207-21 (1982)). However, an immobilizedenzyme-based glucose sensor employing oxygen as co-reactant ispreferably supplied with oxygen in non-rate-limiting excess in order forthe sensor to respond linearly to changes in glucose concentration,while not responding to changes in oxygen concentration. Specifically,when a glucose-monitoring reaction is oxygen limited, linearity is notachieved above minimal concentrations of glucose. Without asemipermeable membrane situated over the enzyme domain to control theflux of glucose and oxygen, a linear response to glucose levels can beobtained only for glucose concentrations of up to about 40 mg/dL.However, in a clinical setting, a linear response to glucose levels isdesirable up to at least about 400 mg/dL.

The resistance domain includes a semipermeable membrane that controlsthe flux of oxygen and glucose to the underlying enzyme domain,preferably rendering oxygen in a non-rate-limiting excess. As a result,the upper limit of linearity of glucose measurement is extended to amuch higher value than that which is achieved without the resistancedomain. In one embodiment, the resistance domain exhibits an oxygen toglucose permeability ratio of from about 50:1 or less to about 400:1 ormore, preferably about 200:1. As a result, one-dimensional reactantdiffusion is adequate to provide excess oxygen at all reasonable glucoseand oxygen concentrations found in the subcutaneous matrix (See Rhodeset al., Anal. Chem., 66:1520-1529 (1994)).

In alternative embodiments, a lower ratio of oxygen-to-glucose can besufficient to provide excess oxygen by using a high oxygen solubilitydomain (for example, a silicone or fluorocarbon-based material ordomain) to enhance the supply/transport of oxygen to the enzyme domain.If more oxygen is supplied to the enzyme, then more glucose can also besupplied to the enzyme without creating an oxygen rate-limiting excess.In alternative embodiments, the resistance domain is formed from asilicone composition, such as is described in U.S. Patent PublicationNo. US-2005-0090607-A1.

In a preferred embodiment, the resistance domain includes a polyurethanemembrane with both hydrophilic and hydrophobic regions to control thediffusion of glucose and oxygen to an analyte sensor, the membrane beingfabricated easily and reproducibly from commercially availablematerials. A suitable hydrophobic polymer component is a polyurethane,or polyetherurethaneurea. Polyurethane is a polymer produced by thecondensation reaction of a diisocyanate and a difunctionalhydroxyl-containing material. A polyurethaneurea is a polymer producedby the condensation reaction of a diisocyanate and a difunctionalamine-containing material. Preferred diisocyanates include aliphaticdiisocyanates containing from about 4 to about 8 methylene units.Diisocyanates containing cycloaliphatic moieties can also be useful inthe preparation of the polymer and copolymer components of the membranesof preferred embodiments. The material that forms the basis of thehydrophobic matrix of the resistance domain can be any of those known inthe art as appropriate for use as membranes in sensor devices and ashaving sufficient permeability to allow relevant compounds to passthrough it, for example, to allow an oxygen molecule to pass through themembrane from the sample under examination in order to reach the activeenzyme or electrochemical electrodes. Examples of materials which can beused to make non-polyurethane type membranes include vinyl polymers,polyethers, polyesters, polyamides, inorganic polymers such aspolysiloxanes and polycarbosiloxanes, natural polymers such ascellulosic and protein based materials, and mixtures or combinationsthereof.

In a preferred embodiment, the hydrophilic polymer component ispolyethylene oxide. For example, one useful hydrophobic-hydrophiliccopolymer component is a polyurethane polymer that includes about 20%hydrophilic polyethylene oxide. The polyethylene oxide portions of thecopolymer are thermodynamically driven to separate from the hydrophobicportions of the copolymer and the hydrophobic polymer component. The 20%polyethylene oxide-based soft segment portion of the copolymer used toform the final blend affects the water pick-up and subsequent glucosepermeability of the membrane.

In some embodiments, the resistance domain is formed from a siliconepolymer modified to allow analyte (e.g., glucose) transport.

In some embodiments, the resistance domain is formed from a siliconepolymer/hydrophobic-hydrophilic polymer blend. In one embodiment, Thehydrophobic-hydrophilic polymer for use in the blend may be any suitablehydrophobic-hydrophilic polymer, including but not limited to componentssuch as polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,polyvinylalcohol, polyacrylic acid, polyethers such as polyethyleneglycol or polypropylene oxide, and copolymers thereof, including, forexample, di-block, tri-block, alternating, random, comb, star,dendritic, and graft copolymers (block copolymers are discussed in U.S.Pat. No. 4,803,243 and U.S. Pat. No. 4,686,044, which are incorporatedherein by reference). In one embodiment, the hydrophobic-hydrophilicpolymer is a copolymer of poly(ethylene oxide) (PEO) and poly(propyleneoxide) (PPO). Suitable such polymers include, but are not limited to,PEO-PPO diblock copolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEOtriblock copolymers, alternating block copolymers of PEO-PPO, randomcopolymers of ethylene oxide and propylene oxide, and blends thereof. Insome embodiments, the copolymers may be optionally substituted withhydroxy substituents. Commercially available examples of PEO and PPOcopolymers include the PLURONIC® brand of polymers available from BASF®.In one embodiment, PLURONIC® F-127 is used. Other PLURONIC® polymersinclude PPO-PEO-PPO triblock copolymers (e.g., PLURONIC® R products).Other suitable commercial polymers include, but are not limited to,SYNPERONICS® products available from UNIQEMA®. U.S. Patent PublicationNo. US-2007-0244379-A1 which is incorporated herein by reference in itsentirety, describes systems and methods suitable for the resistanceand/or other domains of the membrane system of the preferredembodiments.

In preferred embodiments, the resistance domain is deposited onto theenzyme domain to yield a domain thickness of from about 0.05 microns orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. Preferably, the resistancedomain is deposited onto the enzyme domain by vapor deposition, spraycoating, or dip coating. In one preferred embodiment, spray coating isthe preferred deposition technique. The spraying process atomizes andmists the solution, and therefore most or all of the solvent isevaporated prior to the coating material settling on the underlyingdomain, thereby minimizing contact of the solvent with the enzyme.

In another preferred embodiment, physical vapor deposition (e.g.,ultrasonic vapor deposition) is used for coating one or more of themembrane domain(s) onto the electrodes, wherein the vapor depositionapparatus and process include an ultrasonic nozzle that produces a mistof micro-droplets in a vacuum chamber. In these embodiments, themicro-droplets move turbulently within the vacuum chamber, isotropicallyimpacting and adhering to the surface of the substrate. Advantageously,vapor deposition as described above can be implemented to provide highproduction throughput of membrane deposition processes (e.g., at leastabout 20 to about 200 or more electrodes per chamber), greaterconsistency of the membrane on each sensor, and increased uniformity ofsensor performance, for example, as described below.

In some embodiments, depositing the resistance domain (for example, asdescribed in the preferred embodiments above) includes formation of amembrane system that substantially blocks or resists ascorbate (a knownelectrochemical interferant in hydrogen peroxide-measuring glucosesensors). While not wishing to be bound by theory, it is believed thatduring the process of depositing the resistance domain as described inthe preferred embodiments, a structural morphology is formed that ischaracterized in that ascorbate does not substantially permeatetherethrough.

In a preferred embodiment, the resistance domain is deposited on theenzyme domain by spray coating a solution of from about 1 wt. % to about5 wt. % polymer and from about 95 wt. % to about 99 wt. % solvent. Inspraying a solution of resistance domain material, including a solvent,onto the enzyme domain, it is desirable to mitigate or substantiallyreduce any contact with enzyme of any solvent in the spray solution thatcan deactivate the underlying enzyme of the enzyme domain.Tetrahydrofuran (THF) is one solvent that minimally or negligiblyaffects the enzyme of the enzyme domain upon spraying. Other solventscan also be suitable for use, as is appreciated by one skilled in theart.

Although a variety of spraying or deposition techniques can be used,spraying the resistance domain material and rotating the sensor at leastone time by 180° can typically provide adequate coverage by theresistance domain. Spraying the resistance domain material and rotatingthe sensor at least two times by 120° provides even greater coverage(one layer of 360° coverage), thereby ensuring resistivity to glucose,such as is described in more detail above.

In preferred embodiments, the resistance domain is spray coated andsubsequently cured for a time of from about 15 minutes to about 90minutes at a temperature of from about 40° C. to about 60° C. (and canbe accomplished under vacuum (e.g. from 20 to 30 mmHg)). A cure time ofup to about 90 minutes or more can be advantageous to ensure completedrying of the resistance domain.

In one embodiment, the resistance domain is formed by spray coating atleast six layers (namely, rotating the sensor seventeen times by 120°for at least six layers of 360° coverage) and curing at 50° C. undervacuum for 60 minutes. However, the resistance domain can be formed bydip coating or spray coating any layer or plurality of layers, dependingupon the concentration of the solution, insertion rate, dwell time,withdrawal rate, and/or the desired thickness of the resulting film.Additionally, curing in a convention oven can also be employed.

In certain embodiments, a variable frequency microwave oven can be usedto cure the membrane domains/layers. In general, microwave ovensdirectly excite the rotational mode of solvents. Consequently, microwaveovens cure coatings from the inside out rather than from the outside inas with conventional convection ovens. This direct rotational modeexcitation is responsible for the typically observed “fast” curingwithin a microwave oven. In contrast to conventional microwave ovens,which rely upon a fixed frequency of emission that can cause arcing ofdielectric (metallic) substrates if placed within a conventionalmicrowave oven, Variable Frequency Microwave (VFM) ovens emit thousandsof frequencies within 100 milliseconds, which substantially eliminatesarcing of dielectric substrates. Consequently, the membranedomains/layers can be cured even after deposition on metallic electrodesas described herein. While not wishing to be bound by theory, it isbelieve that VFM curing can increase the rate and completeness ofsolvent evaporation from a liquid membrane solution applied to a sensor,as compared to the rate and completeness of solvent evaporation observedfor curing in conventional convection ovens.

In certain embodiments, VFM is can be used together with convection ovencuring to further accelerate cure time. In some sensor applicationswherein the membrane is cured prior to application on the electrode(see, for example, U.S. Patent Publication No. US-2005-0245799-A1, whichis incorporated herein by reference in its entirety), conventionalmicrowave ovens (e.g., fixed frequency microwave ovens) can be used tocure the membrane layer.

Treatment of Interference Domain/Membrane System

Although the above-described methods generally include a curing step information of the membrane system, including the interference domain, thepreferred embodiments further include an additional treatment step,which can be performed directly after the formation of the interferencedomain and/or some time after the formation of the entire membranesystem (or anytime in between). In some embodiments, the additionaltreatment step is performed during (or in combination with)sterilization of the sensor.

In some embodiments, the membrane system (or interference domain) istreated by exposure to ionizing radiation, for example, electron beamradiation, UV radiation, X-ray radiation, gamma radiation, and the like.Alternatively, the membrane can be exposed to visible light whensuitable photoinitiators are incorporated into the interference domain.While not wishing to be bound by theory, it is believed that exposingthe interference domain to ionizing radiation substantially crosslinksthe interference domain and thereby creates a tighter, less permeablenetwork than an interference domain that has not been exposed toionizing radiation.

In some embodiments, the membrane system (or interference domain) iscrosslinked by forming free radicals, which may include the use ofionizing radiation, thermal initiators, chemical initiators,photoinitiators (e.g., UV and visible light), and the like. Any suitableinitiator or any suitable initiator system can be employed, for example,α-hydroxyketone, α-aminoketone, ammonium persulfate (APS), redox systemssuch as APS/bisulfite, or potassium permanganate. Suitable thermalinitiators include but are not limited to potassium persulfate, ammoniumpersulfate, sodium persulfate, and mixtures thereof.

In embodiments wherein electron beam radiation is used to treat themembrane system (or interference domain), a preferred exposure time isfrom about 6 k or 12 kGy to about 25 or 50 kGy, more preferably about 25kGy. However, one skilled in the art appreciates that choice ofmolecular weight, composition of cellulosic derivative (or otherpolymer), and/or the thickness of the layer can affect the preferredexposure time of membrane to radiation. Preferably, the exposure issufficient for substantially crosslinking the interference domain toform free radicals, but does not destroy or significantly break down themembrane or does not significantly damage the underlying electroactivesurfaces.

In embodiments wherein UV radiation is employed to treat the membrane,UV rays from about 200 nm to about 400 nm are preferred; however valuesoutside of this range can be employed in certain embodiments, dependentupon the cellulosic derivative and/or other polymer used.

In some embodiments, for example, wherein photoinitiators are employedto crosslink the interference domain, one or more additional domains canbe provided adjacent to the interference domain for preventingdelamination that may be caused by the crosslinking treatment. Theseadditional domains can be “tie layers” (i.e., film layers that enhanceadhesion of the interference domain to other domains of the membranesystem). In one exemplary embodiment, a membrane system is formed thatincludes the following domains: resistance domain, enzyme domain,electrode domain, and cellulosic-based interference domain, wherein theelectrode domain is configured to ensure adhesion between the enzymedomain and the interference domain. In embodiments whereinphotoinitiators are employed to crosslink the interference domain, UVradiation of greater than about 290 nm is preferred. Additionally, fromabout 0.01 to about 1 wt % photoinitiator is preferred weight-to-weightwith a preselected cellulosic polymer (e.g., cellulose acetate); howevervalues outside of this range can be desirable dependent upon thecellulosic polymer selected.

In general, sterilization of the transcutaneous sensor can be completedafter final assembly, utilizing methods such as electron beam radiation,gamma radiation, glutaraldehyde treatment, and the like. The sensor canbe sterilized prior to or after packaging. In an alternative embodiment,one or more sensors can be sterilized using variable frequency microwavechamber(s), which can increase the speed and reduce the cost of thesterilization process. In another alternative embodiment, one or moresensors can be sterilized using ethylene oxide (EtO) gas sterilization,for example, by treating with 100% ethylene oxide, which can be usedwhen the sensor electronics are not detachably connected to the sensorand/or when the sensor electronics must undergo a sterilization process.In one embodiment, one or more packaged sets of transcutaneous sensors(e.g., 1, 2, 3, 4, or 5 sensors or more) are sterilized simultaneously.

Therapeutic Agents

A variety of therapeutic (bioactive) agents can be used with the analytesensor system of the preferred embodiments, such as the analyte sensorsystem of the embodiments shown in FIGS. 1A-3C. In some embodiments, thetherapeutic agent is an anticoagulant. The term “anticoagulant” as usedherein is a broad term, and is to be given its ordinary and customarymeaning to a person of ordinary skill in the art (and is not to belimited to a special or customized meaning), and refers withoutlimitation to a substance the prevents coagulation (e.g., minimizes,reduces, or stops clotting of blood). In some embodiments, ananticoagulant is included in the analyte sensor system to preventcoagulation within or on the sensor (e.g., within or on the catheter orwithin or on the sensor). Suitable anticoagulants for incorporation intothe sensor system include, but are not limited to, vitamin K antagonists(e.g., Acenocoumarol, Clorindione, Dicumarol (Dicoumarol), Diphenadione,Ethyl biscoumacetate, Phenprocoumon, Phenindione, Tioclomarol, orWarfarin), heparin group anticoagulants (e.g., Platelet aggregationinhibitors: Antithrombin III, Bemiparin, Dalteparin, Danaparoid,Enoxaparin, Heparin, Nadroparin, Parnaparin, Reviparin, Sulodexide,Tinzaparin), other platelet aggregation inhibitors (e.g., Abciximab,Acetylsalicylic acid (Aspirin), Aloxiprin, Beraprost, Ditazole,Carbasalate calcium, Cloricromen, Clopidogrel, Dipyridamole,Epoprostenol, Eptifibatide, Indobufen, Iloprost, Picotamide,Ticlopidine, Tirofiban, Treprostinil, Triflusal), enzymes (e.g.,Alteplase, Ancrod, Anistreplase, Brinase, Drotrecogin alfa,Fibrinolysin, Protein C, Reteplase, Saruplase, Streptokinase,Tenecteplase, Urokinase), direct thrombin inhibitors (e.g., Argatroban,Bivalirudin, Desirudin, Lepirudin, Melagatran, Ximelagatran, otherantithrombotics (e.g., Dabigatran, Defibrotide, Dermatan sulfate,Fondaparinux, Rivaroxaban) and the like.

In one embodiment, heparin is incorporated into the analyte sensorsystem. In a further embodiment, heparin is coated on the catheter(inner and/or outer diameter) and/or sensor, for example, by dipping orspraying. While not wishing to be bound by theory, it is believed thatheparin coated on the catheter and/or sensor prevents aggregation andclotting of blood on the analyte sensor system, thereby preventingthromboembolization (e.g., prevention of blood flow by the thrombus orclot) and/or subsequent complications. In another embodiment, anantimicrobial is coated on the catheter (inner and/or outer diameter)and/or sensor.

In some embodiments, the therapeutic agent is an antimicrobial. The term“antimicrobial agent” as used in the preferred embodiments meansantibiotics, antiseptics, disinfectants and synthetic moieties, andcombinations thereof, that are soluble in organic solvents such asalcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid,methylene chloride and chloroform.

Classes of antibiotics that can be used include tetracyclines (i.e.minocycline), rifamycins (i.e. rifampin), macrolides (i.e.erythromycin), penicillins (i.e. nafeillin), cephalosporins (i.e.cefazolin), other beta-lactam antibiotics (i.e. imipenem, aztreonam),aminoglycosides (i.e. gentamicin), chloramphenicol, sulfonamides (i.e.sulfamethoxazole), glycopeptides (i.e. vancomycin), quinolones (i.e.ciprofloxacin), fusidic acid, trimethoprim, metronidazole, clindamycin,mupirocin, polyenes (i.e. amphotericin B), azoles (i.e. fluconazole) andbeta-lactam inhibitors (i.e. sulbactam).

Examples of specific antibiotics that can be used include minocycline,rifampin, erythromycin, nafcillin, cefazolin, imipenem, aztreonam,gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim,metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin,clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid,sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin,temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid,amphotericin B, fluconazole, itraconazole, ketoconazole, and nystatin.

Examples of antiseptics and disinfectants are hexachlorophene, cationicbisiguanides (i.e. chlorhexidine, cyclohexidine) iodine and iodophores(i.e. povidoneiodine), para-chloro-meta-xylenol, triclosan, furanmedical preparations (i.e. nitrofurantoin, nitrofurazone), methenamine,aldehydes (glutaraldehyde, formaldehyde) and alcohols. Other examples ofantiseptics and disinfectants will readily suggest themselves to thoseof ordinary skill in the art.

These antimicrobial agents can be used alone or in combination of two ormore of them. The antimicrobial agents can be dispersed throughout thematerial of the sensor and/or catheter. The amount of each antimicrobialagent used to impregnate the medical device varies to some extent, butis at least of an effective concentration to inhibit the growth ofbacterial and fungal organisms, such as staphylococci, gram-positivebacteria, gram-negative bacilli and Candida.

In some embodiments, the membrane system of the preferred embodimentspreferably include a bioactive agent, which is incorporated into atleast a portion of the membrane system, or which is incorporated intothe device and adapted to diffuse through the membrane.

There are a variety of systems and methods by which the bioactive agentis incorporated into the membrane of the preferred embodiments. In someembodiments, the bioactive agent is incorporated at the time ofmanufacture of the membrane system. For example, the bioactive agent canbe blended prior to curing the membrane system, or subsequent tomembrane system manufacture, for example, by coating, imbibing,solvent-casting, or sorption of the bioactive agent into the membranesystem. Although the bioactive agent is preferably incorporated into themembrane system, in some embodiments the bioactive agent can beadministered concurrently with, prior to, or after insertion of thedevice intravascularly, for example, by oral administration, or locally,for example, by subcutaneous injection near the implantation site. Acombination of bioactive agent incorporated in the membrane system andbioactive agent administration locally and/or systemically can bepreferred in certain embodiments.

In general, a bioactive agent can be incorporated into the membranesystem, and/or incorporated into the device and adapted to diffusetherefrom, in order to modify the tissue response of the host to themembrane. In some embodiments, the bioactive agent is incorporated onlyinto a portion of the membrane system adjacent to the sensing region ofthe device, over the entire surface of the device except over thesensing region, or any combination thereof, which can be helpful incontrolling different mechanisms and/or stages of thrombus formation. Insome alternative embodiments however, the bioactive agent isincorporated into the device proximal to the membrane system, such thatthe bioactive agent diffuses through the membrane system to the hostcirculatory system.

The bioactive agent can include a carrier matrix, wherein the matrixincludes one or more of collagen, a particulate matrix, a resorbable ornon-resorbable matrix, a controlled-release matrix, and/or a gel. Insome embodiments, the carrier matrix includes a reservoir, wherein abioactive agent is encapsulated within a microcapsule. The carriermatrix can include a system in which a bioactive agent is physicallyentrapped within a polymer network. In some embodiments, the bioactiveagent is cross-linked with the membrane system, while in others thebioactive agent is sorbed into the membrane system, for example, byadsorption, absorption, or imbibing. The bioactive agent can bedeposited in or on the membrane system, for example, by coating,filling, or solvent casting. In certain embodiments, ionic and nonionicsurfactants, detergents, micelles, emulsifiers, demulsifiers,stabilizers, aqueous and oleaginous carriers, solvents, preservatives,antioxidants, or buffering agents are used to incorporate the bioactiveagent into the membrane system. The bioactive agent can be incorporatedinto a polymer using techniques such as described above, and the polymercan be used to form the membrane system, coatings on the membranesystem, portions of the membrane system, and/or any portion of thesensor system.

The membrane system can be manufactured using techniques known in theart. The bioactive agent can be sorbed into the membrane system, forexample, by soaking the membrane system for a length of time (forexample, from about an hour or less to about a week or more, preferablyfrom about 4, 8, 12, 16, or 20 hours to about 1, 2, 3, 4, 5, or 7 days).

The bioactive agent can be blended into uncured polymer prior to formingthe membrane system. The membrane system is then cured and the bioactiveagent thereby cross-linked and/or encapsulated within the polymer thatforms the membrane system.

In yet another embodiment, microspheres are used to encapsulate thebioactive agent. The microspheres can be formed of biodegradablepolymers, most preferably synthetic polymers or natural polymers such asproteins and polysaccharides. As used herein, the term polymer is usedto refer to both to synthetic polymers and proteins. U.S. Pat. No.6,281,015, which is incorporated herein by reference in its entirety,discloses some systems and methods that can be used in conjunction withthe preferred embodiments. In general, bioactive agents can beincorporated in (1) the polymer matrix forming the microspheres, (2)microparticle(s) surrounded by the polymer which forms the microspheres,(3) a polymer core within a protein microsphere, (4) a polymer coatingaround a polymer microsphere, (5) mixed in with microspheres aggregatedinto a larger form, or (6) a combination thereof. Bioactive agents canbe incorporated as particulates or by co-dissolving the factors with thepolymer. Stabilizers can be incorporated by addition of the stabilizersto the factor solution prior to formation of the microspheres.

The bioactive agent can be incorporated into a hydrogel and coated orotherwise deposited in or on the membrane system. Some hydrogelssuitable for use in the preferred embodiments include cross-linked,hydrophilic, three-dimensional polymer networks that are highlypermeable to the bioactive agent and are triggered to release thebioactive agent based on a stimulus.

The bioactive agent can be incorporated into the membrane system bysolvent casting, wherein a solution including dissolved bioactive agentis disposed on the surface of the membrane system, after which thesolvent is removed to form a coating on the membrane surface.

The bioactive agent can be compounded into a plug of material, which isplaced within the device, such as is described in U.S. Pat. No.4,506,680 and U.S. Pat. No. 5,282,844, which are incorporated herein byreference in their entirety. In some embodiments, it is preferred todispose the plug beneath a membrane system; in this way, the bioactiveagent is controlled by diffusion through the membrane, which provides amechanism for sustained-release of the bioactive agent in the host.

Release of Bioactive Agents

Numerous variables can affect the pharmacokinetics of bioactive agentrelease. The bioactive agents of the preferred embodiments can beoptimized for short- and/or long-term release. In some embodiments, thebioactive agents of the preferred embodiments are designed to aid orovercome factors associated with short-term effects (e.g., acuteinflammation and/or thrombosis) of sensor insertion. In someembodiments, the bioactive agents of the preferred embodiments aredesigned to aid or overcome factors associated with long-term effects,for example, chronic inflammation or build-up of fibrotic tissue and/orplaque material. In some embodiments, the bioactive agents of thepreferred embodiments combine short- and long-term release to exploitthe benefits of both.

As used herein, “controlled,” “sustained,” or “extended” release of thefactors can be continuous or discontinuous, linear or non-linear. Thiscan be accomplished using one or more types of polymer compositions,drug loadings, selections of excipients or degradation enhancers, orother modifications, administered alone, in combination or sequentiallyto produce the desired effect.

Short-term release of the bioactive agent in the preferred embodimentsgenerally refers to release over a period of from about a few minutes orhours to about 2, 3, 4, 5, 6, or 7 days or more.

Loading of Bioactive Agents

The amount of loading of the bioactive agent into the membrane systemcan depend upon several factors. For example, the bioactive agent dosageand duration can vary with the intended use of the membrane system, forexample, the intended length of use of the device and the like;differences among patients in the effective dose of bioactive agent;location and methods of loading the bioactive agent; and release ratesassociated with bioactive agents and optionally their carrier matrix.Therefore, one skilled in the art will appreciate the variability in thelevels of loading the bioactive agent, for the reasons described above.

In some embodiments, wherein the bioactive agent is incorporated intothe membrane system without a carrier matrix, the preferred level ofloading of the bioactive agent into the membrane system can varydepending upon the nature of the bioactive agent. The level of loadingof the bioactive agent is preferably sufficiently high such that abiological effect (e.g., thrombosis prevention) is observed. Above thisthreshold, bioactive agent can be loaded into the membrane system so asto imbibe up to 100% of the solid portions, cover all accessiblesurfaces of the membrane, and/or fill up to 100% of the accessiblecavity space. Typically, the level of loading (based on the weight ofbioactive agent(s), membrane system, and other substances present) isfrom about 1 ppm or less to about 1000 ppm or more, preferably fromabout 2, 3, 4, or 5 ppm up to about 10, 25, 50, 75, 100, 200, 300, 400,500, 600, 700, 800, or 900 ppm. In certain embodiments, the level ofloading can be 1 wt. % or less up to about 50 wt. % or more, preferablyfrom about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 wt. % up to about 25,30, 35, 40, or 45 wt. %.

When the bioactive agent is incorporated into the membrane system with acarrier matrix, such as a gel, the gel concentration can be optimized,for example, loaded with one or more test loadings of the bioactiveagent. It is generally preferred that the gel contain from about 0.1 orless to about 50 wt. % or more of the bioactive agent(s), preferablyfrom about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 wt. % to about 6,7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 wt. % or more bioactiveagent(s), more preferably from about 1, 2, or 3 wt. % to about 4 or 5wt. % of the bioactive agent(s). Substances that are not bioactive canalso be incorporated into the matrix.

Referring now to microencapsulate bioactive agents, the release of theagents from these polymeric systems generally occurs by two differentmechanisms. The bioactive agent can be released by diffusion throughaqueous filled channels generated in the dosage form by the dissolutionof the agent or by voids created by the removal of the polymer solventor a pore forming agent during the original micro-encapsulation.Alternatively, release can be enhanced due to the degradation of theencapsulating polymer. With time, the polymer erodes and generatesincreased porosity and microstructure within the device. This createsadditional pathways for release of the bioactive agent.

In some embodiments, the sensor is designed to be bioinert, e.g., by theuse of bioinert materials. Bioinert materials do not substantially causeany response from the host. As a result, cells can live adjacent to thematerial but do not form a bond with it. Bioinert materials include butare not limited to alumina, zirconia, titanium oxide or other bioinertmaterials generally used in the “catheter/catheterization” art. Whilenot wishing to be bound by theory, it is believed that inclusion of abioinert material in or on the sensor can reduce attachment of bloodcells or proteins to the sensor, thrombosis or other host reactions tothe sensor.

Dual-Electrode Analyte Sensors

In general, electrochemical analyte sensors provide at least one workingelectrode and at least one reference electrode, which are configured togenerate a signal associated with a concentration of the analyte in thehost, such as described herein, and as appreciated by one skilled in theart. The output signal is typically a raw data stream that is used toprovide a useful value of the measured analyte concentration in a hostto the patient or doctor, for example. However, the analyte sensors ofthe preferred embodiments may further measure at least one additionalsignal. For example, in some embodiments, the additional signal isassociated with the baseline and/or sensitivity of the analyte sensor,thereby enabling monitoring of baseline and/or sensitivity changes thatmay occur in a continuous analyte sensor over time.

In preferred embodiments, the analyte sensor comprises a first workingelectrode E1 and a second working electrode E2, in addition to areference electrode, which is referred to as a dual-electrode systemherein. The first and second working electrodes may be in any usefulconformation, as described in U.S. Patent Publication No.US-2007-0027385-A1, U.S. Patent Publication No. US-2007-0213611-A1, U.S.Patent Publication No. US-2007-0027284-A1, U.S. Patent Publication No.US-2007-0032717-A1, U.S. Patent Publication No. US-2007-0093704-A1, andU.S. Patent Publication No. US-2008-0083617-A1, each of which isincorporated herein by reference in its entirety. In some preferredembodiments, the first and second working electrodes are twisted and/orbundled. For example, two wire working electrodes can be twistedtogether, such as in a helix conformation. The reference electrode canthen be wrapped around the twisted pair of working electrodes. In somepreferred embodiments, the first and second working electrodes include acoaxial configuration. A variety of dual-electrode system configurationsare described with reference to FIGS. 7A1 through 11 of the referencesincorporated above. In some embodiments, the sensor is configured as adual electrode sensor, such as described in U.S. Patent Publication No.US-2005-0143635-A1, U.S. Patent Publication No. US-2007-0027385-A1, U.S.Patent Publication No. US-2007-0213611-A1, and U.S. Patent PublicationNo. US-2008-0083617-A1, each of which is incorporated herein byreference in its entirety. However, a dual-electrode system can beprovided in any planar or non-planar configuration, such as can beappreciated by one skilled in the art, and can be found in U.S. Pat. No.6,175,752, U.S. Pat. No. 6,579,690, U.S. Pat. No. 6,484,046, U.S. Pat.No. 6,512,939, U.S. Pat. No. 6,477,395, U.S. Pat. No. 6,424,847, U.S.Pat. No. 6,212,416, U.S. Pat. No. 6,119,028, U.S. Pat. No. 6,400,974,U.S. Pat. No. 6,595,919, U.S. Pat. No. 6,141,573, U.S. Pat. No.6,122,536; European Patent Publication No. EP 1153571, U.S. Pat. No.6,512,939, U.S. Pat. No. 5,605,152, U.S. Pat. No. 4,431,004, U.S. Pat.No. 4,703,756, U.S. Pat. No. 6,514,718, U.S. Pat. No. 5,985,129, PCTPatent Publication No. WO04/021877, U.S. Pat. No. 5,494,562, U.S. Pat.No. 6,120,676, and U.S. Pat. No. 6,542,765, each of which areincorporated in there entirety herein by reference in their entirety. Ingeneral, it is understood that the disclosed embodiments are applicableto a variety of continuous analyte measuring device configurations

FIG. 3D illustrates a dual-electrode system in preferred embodiments.The dual-electrode sensor system includes a first working electrode E1and the second working electrode E2, both of which are disposed beneatha sensor membrane M02, such as but not limited to a membrane systemsimilar to that described with reference to FIG. 3C and/or FIGS. 3Fthrough 3I. The first working electrode E1 is disposed beneath an activeenzymatic portion M04 of the sensor membrane M02, which includes anenzyme configured to detect the analyte or an analyte-related compound.Accordingly, the first working electrode E1 is configured to generate afirst signal composed of both signal related to the analyte and signalrelated to non-analyte electroactive compounds (e.g., physiologicalbaseline, interferents, and non-constant noise) that have anoxidation/reduction potential that overlaps with the oxidation/reductionpotential of the analyte. This oxidation/reduction potential may bereferred to as a “first oxidation/reduction potential” herein. Thesecond working electrode E2 is disposed beneath an inactive-enzymatic ornon-enzymatic portion M06 of the sensor membrane M02. The non-enzymaticportion M06 of the membrane includes either an inactivated form of theenzyme contained in the enzymatic portion M04 of the membrane or noenzyme. In some embodiments, the non-enzymatic portion M06 can include anon-specific protein, such as BSA, ovalbumin, milk protein, certainpolypeptides, and the like. The non-enzymatic portion M06 generates asecond signal associated with noise of the analyte sensor. The noise ofthe sensor comprises signal contribution due to non-analyteelectroactive species (e.g., interferents) that have anoxidation/reduction potential that substantially overlaps the firstoxidation/reduction potential (e.g., that overlap with theoxidation/reduction potential of the analyte). In some embodiments of adual-electrode analyte sensor configured for fluid communication with ahost's circulatory system, the non-analyte related electroactive speciescomprises at least one species selected from the group consisting ofinterfering species, non-reaction-related hydrogen peroxide, and otherelectroactive species.

In one exemplary embodiment, the dual-electrode analyte sensor is aglucose sensor having a first working electrode E1 configured togenerate a first signal associated with both glucose and non-glucoserelated electroactive compounds that have a first oxidation/reductionpotential. Non-glucose related electroactive compounds can be anycompound, in the sensor's local environment that has anoxidation/reduction potential substantially overlapping with theoxidation/reduction potential of H₂O₂, for example. While not wishing tobe bound by theory, it is believed that the glucose-measuring electrodecan measure both the signal directly related to the reaction of glucosewith GOx (produces H₂O₂ that is oxidized at the working electrode) andsignals from unknown compounds that are in the blood surrounding thesensor. These unknown compounds can be constant or non-constant (e.g.,intermittent or transient) in concentration and/or effect. In somecircumstances, it is believed that some of these unknown compounds arerelated to the host's disease state. For example, it is known that bloodchemistry changes dramatically during/after a heart attack (e.g., pHchanges, changes in the concentration of various bloodcomponents/protein, and the like). Additionally, a variety ofmedicaments or infusion fluid components (e.g., acetaminophen, ascorbicacid, dopamine, ibuprofen, salicylic acid, tolbutamide, tetracycline,creatinine, uric acid, ephedrine, L-dopa, methyl dopa and tolazamide)that may be given to the host may have oxidation/reduction potentialsthat overlap with that of H₂O₂.

In this exemplary embodiment, the dual-electrode analyte sensor includesa second working electrode E2 that is configured to generate a secondsignal associated with the non-glucose related electroactive compoundsthat have the same oxidation/reduction potential as the above-describedfirst working electrode (e.g., para supra). In some embodiments, thenon-glucose related electroactive species includes at least one ofinterfering species, non-reaction-related H₂O₂, and other electroactivespecies. For example, interfering species includes any compound that isnot directly related to the electrochemical signal generated by theglucose-GOx reaction, such as but not limited to electroactive speciesin the local environment produces by other bodily processes (e.g.,cellular metabolism, a disease process, and the like). Otherelectroactive species includes any compound that has anoxidation/reduction potential similar to or overlapping that of H₂O₂.

The non-analyte (e.g., non-glucose) signal produced by compounds otherthan the analyte (e.g., glucose) obscured the signal related to theanalyte, contributes to sensor inaccuracy, and is considered backgroundnoise. As described in greater detail in the section entitled “NoiseReduction,” background noise includes both constant and non-constantcomponents and must be removed to accurately calculate the analyteconcentration. While not wishing to be bound by theory, it is believedthat the sensor of the preferred embodiments are designed (e.g., withsymmetry, coaxial design and/or integral formation, and interferencedomain of the membrane described elsewhere herein) such that the firstand second electrodes are influenced by substantially the sameexternal/environmental factors, which enables substantially equivalentmeasurement of both the constant and non-constant species/noise. Thisadvantageously allows the substantial elimination of noise on the sensorsignal (using electronics described elsewhere herein) to substantiallyreduce or eliminate signal effects due to noise, including non-constantnoise (e.g., unpredictable biological, biochemical species, medicaments,pH fluctuations, O₂ fluctuations, or the like) known to effect theaccuracy of conventional continuous sensor signals. Preferably, thesensor includes electronics operably connected to the first and secondworking electrodes. The electronics are configured to provide the firstand second signals that are used to generate glucose concentration datasubstantially without signal contribution due to non-glucose-relatednoise. Preferably, the electronics include at least a potentiostat thatprovides a bias to the electrodes. In some embodiments, sensorelectronics are configured to measure the current (or voltage) toprovide the first and second signals. The first and second signals areused to determine the glucose concentration substantially without signalcontribution due to non-glucose-related noise such as by but not limitedto subtraction of the second signal from the first signal or alternativedata analysis techniques. In some embodiments, the sensor electronicsinclude a transmitter that transmits the first and second signals to areceiver, where additional data analysis and/or calibration of glucoseconcentration can be processed. U.S. Patent Publication No.US-2005-0027463-A1, U.S. Patent Publication No. US-2005-0203360-A1 andU.S. Patent Publication No. US-2006-0036142-A1 describe systems andmethods for processing sensor analyte data and are incorporated hereinby reference in their entirety.

In preferred embodiments, the dual-electrode sensor is configured suchthat the first and second working electrodes E1, E2 are equivalentlyinfluenced by in vivo environmental factors. For example, in oneembodiment, the dual-electrode sensor is configured for fluidcommunication with the circulatory system of the host, such as byimplantation in the host's vein or artery via a vascular access device(also referred to as a fluid communication device herein) such as acatheter and/or cannula. When the sensor is contacted with a sample ofthe host's circulatory system (e.g., blood), the first and secondworking electrodes E1, E2 are configured such that they are equivalentlyinfluenced by a variety of environmental factors impinging upon thesensor, such as but not limited to non-analyte related electroactivespecies (e.g., interfering species, non-reaction-related H₂O₂, an otherelectroactive species). Because the first and second working electrodesare equivalently influenced by in vivo environmental factors, the signalcomponent associated with the in vivo environmental factors (e.g.,non-analyte related species with an oxidation/reduction potential thatoverlaps with that of the analyte) can be removed from the signaldetected by the first working electrode (e.g., the first signal). Thiscan give a substantially analyte-only signal. The effects of in vivoenvironmental factors upon the dual-electrode system are discussed ingreater detail elsewhere herein with reference to FIGS. 3G-3I.

In preferred embodiments, the dual-electrode sensor includes electronics(e.g., a processor module, processing memory) that are operablyconnected to the first and second working electrodes and are configuredto provide the first and second signals to generate analyteconcentration data substantially without signal contribution due tonon-analyte-related noise. For example, the sensor electronics processand/or analyze the signals from the first and second working electrodesand calculate the portion of the first electrode signal that is due toanalyte concentration only. The portion of the first electrode signalthat is not due to the analyte concentration can be considered to bebackground, such as but not limited to noise. Accordingly, in oneembodiment of a dual-electrode sensor system configured for fluidcommunication with a host's circulatory system (e.g., via a vascularaccess device) the system comprising electronics operably connected tothe first and second working electrodes; the electronics are configuredto process the first and second signals to generate analyteconcentration data substantially without signal contribution due tonoise.

As a non-limiting example, FIG. 3E illustrates one preferred embodiment,the dual-electrode analyte sensor. In this embodiment, the sensorcomprises a first working electrode E1 configured to detect the analyteand a second working electrode E2, wherein the first and second workingelectrodes are formed of two wire working electrodes twisted together toform a “twisted pair.” The first working electrode E1 is disposedbeneath an enzymatic portion of the membrane (not shown) containing ananalyte-detecting enzyme. For example, in a glucose-detectingdual-electrode analyte sensor, a glucose-detecting enzyme, such as GOX,is included in the enzymatic portion of the membrane. Accordingly, thefirst working electrode E1 detects signal due to both the analyte andnon-analyte-related species that have an oxidation/reduction potentialthat substantially overlaps with the oxidation/reduction potential ofthe analyte. The second working electrode E2 is disposed beneath aportion of the membrane comprising either inactivated enzyme (e.g.,inactivated by heat, chemical or UV treatment) or no enzyme.Accordingly, the second working electrode E2 detects a signal associatedwith only the non-analyte electroactive species that have anoxidation/reduction potential that substantially overlaps with that ofanalyte. For example, in the glucose-detecting dual-electrode analytesensor described above, the non-analyte (e.g., non-glucose)electroactive species have an oxidation/reduction potential thatoverlaps substantially with that of H₂O₂. A reference electrode R, suchas a silver/silver chloride wire electrode, is wrapped around thetwisted pair. The three electrodes E1, E2 and R are connected to sensorelectronics (not shown), such as described elsewhere herein. Inpreferred embodiments, the dual-electrode sensor is configured toprovide an analyte-only signal (e.g., glucose-only signal) substantiallywithout a signal component due to the non-analyte electroactive species(e.g., noise). For example, the dual-electrode sensor is operablyconnected to sensor electronics that process the first and secondsignals, such that a substantially analyte-only signal is provided(e.g., output to a user). In other exemplary embodiments, thedual-electrode sensor can be configured for detection of a variety ofanalytes other than glucose, such as but not limited to urea,creatinine, succinate, glutamine, oxygen, electrolytes, cholesterol,lipids, triglycerides, hormones, liver enzymes, and the like.

With reference to the analyte sensor embodiments disclosed herein, thesurface area of the electroactive portion of the reference (and/orcounter) electrode is at least six times the surface area of the workingelectrodes. In other embodiments, the reference (and/or counter)electrode surface is 1, 2, 3, 4, 5, 7, 8, 9 or 10 times the surface areaof the working electrodes. In other embodiments, the reference (and/orcounter) electrode surface area is 11, 12, 13, 14, 15, 16, 17, 18, 19 or20 times the surface area of the working electrodes. For example, in aneedle-type glucose sensor, similar to the embodiment shown in FIG. 3E,the surface area of the reference electrode (e.g., R) includes theexposed surface of the reference electrode, such as but not limited tothe electrode surface facing away from the working electrodes E1, E2.

In various embodiments, the electrodes can be stacked or grouped similarto that of a leaf spring configuration, wherein layers of electrode andinsulator (or individual insulated electrodes) are stacked in offsetlayers. The offset layers can be held together with bindings ofnon-conductive material, foil, or wire. As is appreciated by one skilledin the art, the strength, flexibility, and/or other material property ofthe leaf spring-configured or stacked sensor can be either modified(e.g., increased or decreased), by varying the amount of offset, theamount of binding, thickness of the layers, and/or materials selectedand their thicknesses, for example. Alternative dual-electrodeconfigurations include those illustrated in FIGS. 2G-2S, as describedherein.

In preferred embodiments, the analyte sensor substantially continuouslymeasures the host's analyte concentration. In some embodiments, forexample, the sensor can measure the analyte concentration every fractionof a second, about every fraction of a minute or every minute. In otherexemplary embodiments, the sensor measures the analyte concentrationabout every 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes. In still otherembodiments, the sensor measures the analyte concentration everyfraction of an hour, such as but not limited to every 15, 30 or 45minutes. Yet in other embodiments, the sensor measures the analyteconcentration about every hour or longer. In some exemplary embodiments,the sensor measures the analyte concentration intermittently orperiodically. In one preferred embodiment, the analyte sensor is aglucose sensor and measures the host's glucose concentration about every4-6 minutes. In a further embodiment, the sensor measures the host'sglucose concentration every 5 minutes.

As a non-limiting example, dual-electrode glucose sensor can bemanufactured as follows. In one embodiment, the working electrodes arefirst coated with a layer of insulating material (e.g., non-conductivematerial or dielectric) to prevent direct contact between the workingelectrodes E1, E2 and the reference electrode R. At this point, or atany point hereafter, the two working electrodes can be twisted and/orbundled to form a twisted pair. A portion of the insulator on anexterior surface of each working electrode is etched away, to expose theelectrode's electroactive surface. In some embodiments, an enzymesolution (e.g., containing active GOx) is applied to the electroactivesurfaces of both working electrodes, and dried. Thereafter, the enzymeapplied to one of the electroactive surfaces is inactivated. As is knownin the art, enzymes can be inactivated by a variety of means, such as byheat, treatment with inactivating (e.g., denaturing) solvents,proteolysis, laser irradiation or UV irradiation (e.g., at 254-320 nm).For example, the enzyme coating one of the electroactive surfaces can beinactivated by masking one of the electroactive surfaces (e.g.,electrodes, E1, temporarily covered with a UV-blocking material);irradiating the sensor with UV light (e.g., 254-320 nm; a wavelengththat inactivates the enzyme, such as by cross-linking amino acidresidues) and removing the mask. Accordingly, the GOx on E2 isinactivated by the UV treatment, but the E1 GOx is still active due tothe protective mask. In other embodiments, an enzyme solution containingactive enzyme is applied to a first electroactive surface (e.g., E1) andan enzyme solution containing either inactivated enzyme or no enzyme isapplied to the second electroactive surface (e.g., E2). Thus, theenzyme-coated first electroactive surface (e.g., E1) detectsanalyte-related signal and non-analyte-related signal; while the secondelectroactive surface (e.g., E2), which lacks active enzyme, detectsnon-analyte-related signal. As described herein, the sensor electronicscan use the data collected from the two working electrodes to calculatethe analyte-only signal.

In some circumstances, cross talk can interfere with analyte/noisedetection. In general, cross talk occurs when signal (e.g., in the formof energy and/or a detectable species such as but not limited to H₂O₂)is transferred from one electrode (e.g., the first working electrode) toanother (e.g., the second working electrode), and detected as a signalby the other electrode. To prevent cross talk, in preferred embodiments,the first and second working electrodes E1, E2 are separated bydiffusion barrier, such as an insulator, a non-conductive material, areference electrode and/or the like.

FIG. 3F illustrates the use of a diffusion barrier to prevent cross talkin a dual-electrode glucose sensor, in one embodiment. The first andsecond working electrodes E1, E2 are disposed beneath a membrane 348 andseparated by a diffusion barrier D. Within the membrane, glucose ismetabolized by the GOx enzyme, which produces H₂O₂. The H₂O₂ produced bythe enzymatic reaction can diffuse in any direction through the membrane348. A portion of the H₂O₂ diffuses to the surface of the first workingelectrode and is detected due to the transfer of two electrons to theelectrode. Another portion of the H₂O₂ can diffuse out of the membrane.Since the diffusion barrier D is disposed between the workingelectrodes, the diffusion barrier substantially blocks diffusion of H₂O₂to the second working electrode E2. If no diffusion barrier werepresent, the H₂O₂ would be able to diffuse to the second workingelectrode E2 and cause a signal also referred to as cross talk. Avariety of diffusion barriers can be employed to prevent cross talk. Insome embodiments, the diffusion barrier D is a physical diffusionbarrier, such as a structure between the working electrodes that blocksglucose and H₂O₂ from diffusing from the first working electrode E1 tothe second working electrode E2. In other embodiments, the diffusionbarrier D is a spatial diffusion barrier, such as a distance between theworking electrodes that blocks glucose and H₂O₂ from diffusing from thefirst working electrode E1 to the second working electrode E2. In stillother embodiments, the diffusion barrier D is a temporal diffusionbarrier, such as a period of time between the activity of the workingelectrodes such that if glucose or H₂O₂ diffuses from the first workingelectrode E1 to the second working electrode E2, the second workingelectrode E2 will not substantially be influenced by the H₂O₂ from thefirst working electrode E1.

Accordingly, in some preferred embodiments, the dual-electrode sensorcomprises an insulator, such as an electrical insulator, located betweenthe first and second working electrodes, wherein the insulator comprisesa physical diffusion barrier. The physical diffusion barrier isconfigured to structurally block a substantial amount of diffusion of atleast one of an analyte (e.g., glucose) and a co-analyte (e.g., H₂O₂)between the first and second working electrodes. In some embodiments,the diffusion barrier comprises a structure that protrudes from a planethat intersects both the first and second working electrodes. In afurther embodiment, the structure that protrudes comprises an electricalinsulator and/or an electrode.

In some preferred embodiments, the dual-electrode sensor comprises aninsulator located between the first and second working electrodes,wherein the insulator comprises a diffusion barrier configured tosubstantially block diffusion of at least one of an analyte and aco-analyte between the first and second working electrodes. In preferredembodiments, the diffusion barrier comprises a temporal diffusionbarrier configured to block or avoid a substantial amount of diffusionor reaction of at least one of the analyte and the co-analyte betweenthe first and second working electrodes.

In still other preferred embodiments, the dual-electrode sensorcomprises a sensor membrane configured to substantially block diffusionof at least one of an analyte and a co-analyte between the first andsecond working electrodes by a discontinuity of the sensor membranebetween the first and second working electrodes. A discontinuity of thesensor membrane is a type of physical diffusion barrier formed by aportion of the membrane between the two working electrodes, in someembodiments, wherein a discontinuity in the membrane structure blocksdiffusion of H₂O₂ between the electrodes. Discontinuities of sensormembranes are discussed in greater detail with reference to FIG. 3I, inthe section entitled “Sensor Configurations for Equivalent Measurementof Noise.”

In some embodiments, the dual-electrode sensor system is configured forfluid communication with a host's circulatory system, such as via avascular access device. A variety of vascular access devices suitablefor use with a dual-electrode analyte sensor are described elsewhereherein. In some embodiments, the vascular access device comprises alumen and at least a portion of the sensor is disposed within the lumen;and in some embodiments, at least a portion of the sensor can extendinto the vascular system. In some embodiments, the vascular accessdevice comprises a hub and the continuous analyte sensor is disposedsubstantially within the hub. In some embodiments, the system includes afluid coupler configured and arranged to mate with the vascular accessdevice on a first end; wherein the sensor is disposed within a portionof the fluid coupler and/or at a surface of the fluid coupler. In someembodiments, the sensor is configured to reside substantially above aplane defined by the host's skin. In some embodiments, the sensor isdisposed on a surface of the vascular access device. In someembodiments, the vascular access device is configured for insertion intoat least one of an artery, a vein, a fistula, and an extracorporealcirculatory device configured to circulate at least a portion of thehost's blood outside of the host's body. In some embodiments, the systemincludes a flow control device in fluid communication with the vascularaccess device. The flow control device is configured to meter a flow ofa fluid (e.g., blood, saline, a reference solution) through the vascularaccess device. In some embodiments, the flow control device is furtherconfigured to control fluid contact with the continuous analyte sensor,as is described in the section entitled “Integrated Sensor System.”

In preferred embodiments, the sensor electronics (e.g., electroniccomponents) are operably connected to the first and second workingelectrodes. The electronics are configured to calculate at least oneanalyte sensor data point. For example, the electronics can include apotentiostat, A/D converter, RAM, ROM, transmitter, and the like. Insome embodiments, the potentiostat converts the raw data (e.g., rawcounts) collected from the sensor to a value familiar to the host and/ormedical personnel. For example, the raw counts from a glucose sensor canbe converted to milligrams of glucose per deciliter of glucose (e.g.,mg/dl). In some embodiments, the electronics are operably connected tothe first and second working electrodes and are configured to processthe first and second signals to generate a glucose concentrationsubstantially without signal contribution due to non-glucose noiseartifacts. The sensor electronics determine the signals from glucose andnon-glucose related signal with an overlapping measuring potential(e.g., from a first working electrode) and then non-glucose relatedsignal with an overlapping measuring potential (e.g., from a secondelectrode). The sensor electronics then use these data to determine asubstantially glucose-only concentration, such as but not limited tosubtracting the second electrode's signal from the first electrode'ssignal, to give a signal (e.g., data) representative of substantiallyglucose-only concentration, for example. In general, the sensorelectronics may perform additional operations, such as but not limitedto data smoothing and noise analysis.

In preferred embodiments, the dual-electrode sensor includes electronics(e.g., a processor module, processing memory) that are operablyconnected to the first and second working electrodes and are configuredto provide the first and second signals to generate an analyteconcentration data substantially without signal contribution due tonon-analyte-related noise. For example, the sensor electronics processand/or analyze the signals from the first and second working electrodesand calculate the portion of the first electrode signal that is due toanalyte concentration only. The portion of the first electrode signalthat is not due to the analyte concentration can be considered to bebackground, such as but not limited to noise. Accordingly, in oneembodiment of a dual-electrode sensor system configured for fluidcommunication with a host's circulatory system (e.g., via a vascularaccess device) the system comprising electronics operably connected tothe first and second working electrodes; the electronics are configuredto process the first and second signals to generate analyteconcentration data substantially without signal contribution due tonoise.

In some embodiments, the dual-electrode analyte sensor includes areference sensor/system, as described elsewhere therein, wherebyreference data can be provided for calibration (e.g., internal to thesystem), without the use of an external (e.g., separate from the system)analyte-measuring device. In an exemplary embodiment, the dual-electrodesensor is a glucose sensor and external glucose data points (e.g., froma hand-held glucose meter or a YSI device) are not required forcalibration of a dual-electrode glucose sensor system that includes areference sensor. In some embodiments, the reference sensor isconfigured to be disposed within the same local environment as thedual-electrode analyte sensor, such that the reference sensor and thedual-electrode analyte sensor can be simultaneously exposed to a sample.In some embodiments, the reference sensor/system can be disposedremotely from the dual-electrode sensor. In these embodiments, theelectronics module is configured to process the reference data with thefirst and second signals to generate analyte concentration datasubstantially without signal contribution due to noise. In someembodiments, the electronics module is configured to calibrate thedual-electrode analyte sensor data using the reference sensor data, asdescribed elsewhere herein.

In some embodiments, the electronics module is configured to determine ascaling factor (k) as described in the section entitled “CalibrationSystems and Methods.” Briefly, a scaling factor defines a relationshipbetween the enzymatic portion of the membrane and the non-enzymaticportion of the membrane. Accordingly, in some embodiments, theelectronics module, also referred to as the processor module herein, isconfigured to and/or comprises programming to calibrate the analytesensor data using the scaling factor, such that the calibrated sensordata does not include inaccuracies that can arise due to smalldifferences between the plus- and minus-enzyme portions of the membraneat the first and second working electrodes, respectively.

In some embodiments, the system is configured to calibrate thecontinuous dual-electrode analyte sensor using a reference fluid (e.g.,602 a), as described in the section entitled “integrated sensor system.”In some embodiments, the system is configured to calibrate the sensorusing single-point calibration, in other embodiments, the system isconfigured to calibrate the sensor without a reference data pointprovided by an external analyte monitor (e.g., SMBG, YSI), as describedelsewhere herein. In some embodiments, the system includes a referencesensor configured to generate a signal associated with a referenceanalyte in the sample (e.g., internal to the system), wherein thecontinuous analyte sensor is further configured to generate a thirdsignal associated with the reference analyte, and wherein the system isconfigured to calibrate the continuous analyte sensor using thereference signal and the third signal. In some embodiments, thereference sensor comprises an optical sensing apparatus, such as but notlimited to an optical O₂ sensor. In preferred embodiments, thecontinuous analyte sensor is a glucose sensor. In other embodiments, asubstantial portion of the continuous analyte sensor has a diameter ofless than about 0.008 inches, as is described elsewhere herein.

In some further embodiments, the continuous analyte sensor furthercomprises a bioinert material or a bioactive agent incorporated thereinor thereon. Applicable bioactive agent include but are not limited tovitamin K antagonists, heparin group anticoagulants, plateletaggregation inhibitors, enzymes, direct thrombin inhibitors, Dabigatran,Defibrotide, Dermatan sulfate, Fondaparinux, and Rivaroxaban.

As a non-limiting example, in some preferred embodiments, a method forcontinuously detecting an analyte in the host in vivo using adual-electrode analyte sensor is provided. In some embodiments, avascular access device (e.g., a catheter) is inserted into the host'scirculatory system, such as into a vein or artery. The sensor iscontacted with a sample of the circulatory system, such as a sample ofblood withdrawn into the catheter. A first signal is generated by thesensor, wherein the first signal is associated with associated with theanalyte and non-analyte related electroactive compounds having a firstoxidation/reduction potential in a sample of the circulatory system ofthe host. In preferred embodiments, the analyte sensor is configured todetect glucose. A second signal is also generated, wherein the secondsignal is associated with noise of the analyte sensor, wherein the noisecomprises signal contribution due to non-analyte related electroactivespecies with an oxidation/reduction potential that substantiallyoverlaps with the first oxidation/reduction potential in the sample. Thefirst and second signals are processed to provide a processed signalsubstantially without a signal component associated with noise. In someembodiments, the first and second signals are processed to provide ascaling factor, which can then be used to calibrate the first signal. Insome embodiments, a reference sensor is also contacted with the sample,and a third signal associated with a reference analyte generated. Insome embodiments, the reference sensor is an optical detectionapparatus, such as but not limited to an optical O₂ sensor. In thisembodiment, the first and second signals can be calibrated using thethird and/or reference signal. In some preferred embodiments, theprocessing step comprises evaluating steady-state information andtransient information, wherein the first and second signals eachcomprise steady-state and transient information. In some furtherembodiments, the evaluating step includes evaluating at least one ofsensitivity information and baseline information, wherein thesteady-state information comprises the sensitivity and baselineinformation.

Optical Detection

In some embodiments, the continuous analyte sensor is configured todetect the analyte by optical means. In some embodiments, various typesof Raman and/or fluorescent spectroscopic detection are used. Forexample, glucose can be detected via fiber optic visible fluorescence,using glucose dehydrogenase (GDH) and a modified flavin adeninedinucleotide (FAD) coenzyme system, Concanavalin A, or hexokinase. Insome embodiments, a fluorescent molecule (e.g., a fluorophore) isattached to the co-enzyme or to a hydrogen peroxide end-productreactant, as in a calorimetric detection system. In an alternativeembodiment, ferrocene is modified and used as a mediator in the reactionof GOX (or GHD) with glucose, wherein a pH-sensitive fluorophore is usedto detect the reaction. In some embodiments, fiber optic probes areconstructed by applying membrane systems configured foroptical/fluorescent detection to an optical fiber. In some embodiments,multiple fiber optic probes are bundled, which enables a variety ofintegrative and/or subtractive signal correlations/corrections and toenhance error detection. Examples of optical detection can be found inU.S. Pat. No. 7,289,836 and U.S. Pat. No. 7,149,562, each of which isincorporated by reference herein in its entirety.

Sensor Signal Generation

In some embodiments, a continuous analyte detection system is provided,including a sensor configured and arranged for fluid contact with ahost's circulatory system and a processor module. The sensor comprisesboth a continuous analyte sensor (e.g., either non-dual-electrode ordual-electrode) and a reference sensor. For example, in some embodimentsthe system includes a continuous analyte sensor including a workingelectrode and a reference electrode, and a reference sensor. In otherembodiments, the system includes a dual-electrode analyte sensor,including first and second working electrodes and a reference electrode,and a reference sensor. The continuous analyte sensor is configured andarranged to generate a first signal associated with a test analyte and asecond signal associated with a reference analyte. For example, in oneembodiment, the test analyte is glucose and the reference analyte isoxygen; thus, the first signal is associated with glucose and thereference signal is associated with oxygen. The reference sensor isconfigured to generate a reference signal that is also associated withthe reference analyte. In general, a “reference analyte” can be anyanalyte that can be measured by both the analyte sensor and thereference sensor, such those analytes listed under the definition of“analyte” in the section entitled “Definitions.” In preferredembodiments, the reference analyte is one that is relatively stablewithin the host's body, such as but not limited to O₂, succinate,glutamine, and the like. In this embodiment, the processor module isconfigured to and/or comprises programming to process the second signal(e.g., related to the reference analyte) and the reference signal tocalibrate the first signal (e.g., related to the analyte). In someembodiments, the processor module calibrates the second signal (e.g.,the reference analyte signal detected by the analyte sensor) using thereference signal provided by the reference sensor, and then to calibratethe first signal (e.g., the analyte signal) using the second signal.

As a non-limiting example, in some embodiments, the system's continuousanalyte sensor is a dual-electrode sensor that comprises both first andsecond working electrodes E1, E2. Accordingly, the first workingelectrode is disposed beneath an active enzymatic portion of a sensormembrane and generates a signal (e.g., the first signal) associated withboth the analyte (e.g., glucose) and non-analyte related electroactivecompounds (e.g., non-glucose compounds that have an oxidation/reductionpotential that substantially overlaps with the oxidation/reductionpotential of glucose). Additionally, the second working is disposedbeneath an inactive-enzymatic or a non-enzymatic portion of the sensormembrane and generates a non-analyte-related signal associated with thenon-analyte electroactive species. In this embodiment, the processormodule configured to and/or comprises programming to process signalsfrom the first and second working electrodes, and to thereby generate afirst signal substantially without a non-analyte signal component.

The second signal (e.g., related to the reference analyte) can begenerated by various means. For example, in some embodiments, the firstworking electrode of the dual-electrode analyte sensor is configured togenerate both the first signal and the second signal. For example, insome embodiments, pulsed amperometric detection, including switching,cycling or pulsing the voltage of the electrode in an electrochemicalsystem (e.g., between a positive voltage (e.g., +0.6 for detectingglucose) and a negative voltage (e.g., −0.6 for detecting oxygen)) canbe employed to determine an oxygen measurement. For example, the firstworking electrode is configured to generate a signal associated with theanalyte when a potential of +0.6 mV is applied thereto. If the potentialis switch to −0.6 mV, then the first working electrode becomes an O₂sensor and measures a signal associate with the amount of O₂ passingthrough the sensor's membrane system. U.S. Pat. No. 4,680,268, which isincorporated by reference herein, described pulsed amperometricdetection in greater detail. Additional oxygen sensors are described inU.S. Pat. No. 6,512,939, which is incorporated herein by reference.

As a non-limiting example, in one embodiment the dual-electrode analytesensor is a glucose sensor configured for fluid communication with ahost's circulatory system, wherein the sensor is configured to generatea first signal associated with glucose (at the first working electrodeE1) at an applied potential of 0.6 mV, and then to generate a secondsignal associated with O₂ (also at the first working electrode E1) at anapplied potential of −0.6 mV. Thus, in some embodiments, the potentialapplied to the first working electrode can be switched from +0.6 mV to−0.6 mV, such that the first working electrode switches from measuringthe analyte-related signal (e.g., glucose) to measuring the secondsignal (e.g., associated with O₂).

In some alternative embodiments, the second working electrode E2 (e.g.,instead of the first working electrode E1) is configured to generate thesecond signal. As a non-limiting example, in another embodiment thedual-electrode analyte sensor is a glucose sensor configured for fluidcommunication with a host's circulatory system, wherein the sensor isconfigured to generate a first signal associated with glucose (at thefirst working electrode E1) at an applied potential of 0.6 mV, togenerate a non-analyte-related signal (at the second working electrodeE2) at an applied potential of 0.6 mV, and then to generate a secondsignal associated with O₂ (also at the second working electrode E2) atan applied potential of −0.6 mV. Thus, in some embodiments, thepotential applied to the second working electrode can be switched from0.6 mV to −0.6 mV, such that the second working electrode switches frommeasuring the non-analyte-related signal to measuring the second signal(e.g., associated with O₂).

In still other embodiments, the second signal can be generated by athird working electrode disposed beneath the sensor's membrane. As anon-limiting example, in another embodiment the dual-electrode analytesensor is a glucose sensor configured for fluid communication with ahost's circulatory system, wherein the sensor is configured to generatea first signal associated with glucose (at the first working electrodeE1) at an applied potential of 0.6 mV, to generate a non-analyte-relatedsignal (at the second working electrode E2) at an applied potential of0.6 mV, and then to generate the second signal associated with O₂ (atthe third working electrode, e.g., E3, not shown) at an appliedpotential of −0.6 mV. Thus, in some embodiments, switching the appliedpotential from 0.6 mV to −0.6 mV is not required.

As described above, the system includes a reference sensor. In someembodiments, the reference sensor is an optical sensing apparatus, asdescribed above. In other embodiments, the reference sensor isconfigured to detect the reference analyte by any means known in theart, such as but not limited to electrochemical, chemical, physical,immunochemical, calorimetric and/or radiometric means. Preferably, thereference sensor is disposed in the same local environment as thecontinuous analyte sensor, but not under the membrane system of thecontinuous analyte sensor. For example, the reference sensor can bedisposed adjacent to the continuous analyte sensor, such that when thecontinuous analyte sensor is contacted with a sample the referencesensor is simultaneously contacted by the sample. As a non-limitingexample, in some embodiments, a dual-electrode continuous analyte sensorand a reference sensor are disposed adjacently, such that they can besimultaneously exposed to a sample of the host's circulatory system.

As a non-limiting example, in some embodiments, a dual-electrode sensorincludes a first working electrode configured to detect the analyte(including non-analyte-related noise) and a second working electrode isconfigured to detect the signal associated with non-analyte-relatednoise. In some embodiments, the first and second working electrodes arebundled and/or twisted, and the reference sensor is disposed adjacent tothe first and second working electrodes. In some embodiments, either thefirst or the second working electrodes of the dual-electrode sensor isconfigured to detect a signal associated with the reference analyte(e.g., a second signal); while in other embodiments, the dual-electrodesensor includes a third working electrode configured to detect thereference analyte (e.g., the second signal).

As a non-limiting example, in one embodiment of a system comprising botha dual-electrode sensor and an optical reference sensor, thedual-electrode sensor is both a glucose sensor and an O₂ sensor, and thereference sensor is an optical O₂ sensor. Accordingly, as describedelsewhere herein, the first working electrode of the dual-electrodesensor is configured to detect a signal associated with both glucose andnon-glucose-related electroactive species (in a sample of the host'scirculatory system), and the second working electrode is configured todetect the non-glucose related electroactive species. Either the firstworking electrode or the second working electrode is configured todetect O₂, such as via switching the applied potential from 0.6 mV to−0.6 MV, as described elsewhere herein. The reference sensor, which canbe bundled with the dual-electrode sensor, is configured to opticallydetect a reference signal associated with the O₂ concentration of thesample. In some embodiments, instead of using the first or secondworking electrodes to detect O₂, the dual-electrode sensor includes athird electrode configured to detect O₂.

In preferred embodiments, the signal related to a reference analyte(e.g., O₂) can be used to calibrate the signals from a continuousanalyte sensor, such as in the event of a drift in sensor sensitivityand/or baseline. Accordingly, the signals related to the referenceanalyte, from the continuous analyte and reference sensors, can beprocessed to determine a calibration factor. The calibration factor canthen be used to calibrate the continuous analyte sensor data. As usedherein, the term “calibration factor” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a mathematicalfunction generated by processing the reference analyte-related signal ofthe continuous analyte sensor and the reference analyte-related signalof the reference sensor, which can be used to calibrate the continuousanalyte sensor data initially and/or responsive to an occurrence of adrift in sensor sensitivity and/or baseline.

In some embodiments, a method for measuring an analyte in a host isprovided. First, a continuous analyte detection system, which includes acontinuous analyte sensor and a reference sensor, is provided. Inpreferred embodiments, the continuous analyte sensor is configured andarranged to generate a first signal associated with a test analyte(e.g., glucose) and a second signal associated with a reference analyte(e.g., O₂), and the reference sensor configured to generate a referencesignal associated with the reference analyte (e.g., O₂).

Next, the detection system is exposed to a sample of a host'scirculatory system in vivo. For example, the detection system can befluidly coupled to a vascular access device implanted in a host'scirculatory system, such that a sample of the host's blood can be drawnback an contacted with the detection system. Preferably, the continuousanalyte sensor and the reference sensor are exposed to the samplesimultaneously. Accordingly, measurements of the reference analyte canbe made at the same time by the continuous analyte and referencesensors. In some embodiments, a fluid flow device configured for fluidcommunication with the circulatory system of the host and to meter aflow of a fluid therethrough is provided. In these embodiments, thefluid flow device comprises a vascular access device configured forinsertion into either an artery or a vein of the host. Such fluid flowdevices are described in detail in the sensor entitled “IntegratedSensor System.” In preferred embodiments, the fluid flow device iscoupled with the continuous analyte detection system, and a sample ofthe circulatory system of the host is withdrawn. In some preferredembodiments, the fluid flow device is further configured to meter theflow of a non-bodily fluid through the vascular access device.Non-bodily fluids include a variety of sterile infusion fluids, such asbut are not limited to saline, reference solutions such as a glucosesolution of defined concentration, nutritional supplements, IVmedicaments, and the like.

When the sample contacts the system, signals are received from thecontinuous analyte sensor and the reference sensor. The signals receivedinclude a first signal (e.g., related to the test analyte, such as butnot limited to glucose), a second signal (e.g., related to the referenceanalyte, such as but not limited to O₂) and a reference signal (e.g.,related to the reference analyte). In some embodiments, the first signalis received from a first working electrode disposed under an enzymaticportion of a membrane system. For example, in the case of a glucosedetection system, the first working electrode is disposed beneath aportion of the membrane system including active GOX and detects a firstsignal associated with the concentration of glucose in the sample. Insome embodiments, the first working electrode also received the secondsignal, as described elsewhere herein. In other embodiments, the secondsignal is received from a second working electrode that is also disposedunder the membrane system. In some embodiments, the second workingelectrode configured to also receive a non-analyte-related signal. Forexample, the second working electrode is disposed under a non-enzymaticportion of the membrane system, in some embodiments. In some otherembodiments, the non-analyte-related signal is received from a thirdworking electrode disposed under a non-enzymatic portion of the membranesystem. In some embodiments, the reference sensor is configured todetect the reference analyte optically. For example, in someembodiments, the reference analyte is oxygen. Accordingly, the secondsignal and the reference signal received are associated with theconcentration of oxygen in the sample.

After the signals have been received, a calibration factor iscalculated, wherein the calibration factor is associated with asensitivity and/or baseline of the continuous analyte sensor. Forexample, in some embodiments, the continuous analyte detection system isexposed to a bodily fluid (e.g., blood) and the calculating stepincludes comparing steady-state information of the first signal andsteady-state information of the second signal. In some embodiments, thecalibration factor can be calculated by examining the transientinformation of the first and second signals.

In some other embodiments, the continuous analyte detection system isconfigured to be exposed to a non-bodily fluid, such as saline or areference fluid, such as to wash the previous blood sample off of thedevice. During the washing procedure, the non-bodily fluid can be heldsubstantially stagnant (e.g., no flow or very little flow of the fluidpast the sensor) for a period of time. During this period of time, theworking electrodes of the continuous analyte sensor detect signalsassociated with non-analyte-related compounds diffusion to the first andsecond working electrodes. For example, in some embodiments, a salinesolution containing a defined amount of glucose is used to wash thesensor. When the glucose-containing saline is held stagnant (e.g., afterwashing the previous sample off of the sensor), the GOX at the firstworking electrode metabolizes glucose diffusing through the membrane. Asthe glucose is metabolized, the reactant (e.g., H₂O₂) begins toaccumulate and produce signals at both the first and second workingelectrodes. As a result, the signal increase on each of the first andsecond working electrodes (e.g., during the time period) can be comparedto calculate the calibration factor. This method for calculating thecalibration factor is discussed in greater detail elsewhere herein, withreference to FIGS. 3J and 3K.

After the calibration factor has been calculated, the signal(s) from thecontinuous analyte sensor are calibrated using the calibration factor.The process of calculating the calibration factor and then using thenewly calculated calibration factor to calibrate the signals can becontinuous, continual and/or intermittent; such that at time passes thecalibration factor and calibration are updated. Thus, the system isconfigured to evaluate changes in membrane sensitivity and/or baseline,to adjust the calculation of analyte concentrations accordingly, wherebythe host is provided with more accurate data for use in therapydecision-making.

Multi-Sensor Apparatus

In some preferred embodiments, a multi-sensor apparatus configured forthe detection of a plurality of analytes in a circulatory system of ahost in vivo is provided. FIGS. 2G through 2S illustrate some exemplaryembodiments of such a device. In preferred embodiments, the multi-sensorapparatus is a vascular access device (e.g., a catheter) or a connectorconfigured for fluid communication with the circulatory system of thehost. Preferably, the multi-sensor apparatus includes a lumen (e.g., aduct) sufficiently large to house the plurality of sensors, as describedelsewhere herein. In an exemplary embodiment, the multi-sensor apparatuscomprises a plurality of analyte sensors, wherein the plurality ofanalyte sensor are configured to detect at least one analyte and tocontact a sample of the host's circulatory system. In one exemplaryembodiment, the multi-sensor apparatus comprises a lumen, an externalsurface, and two orifices, wherein a first orifice is proximal relativeto the host and the second orifice is distal. In some embodiments, suchas in a catheter, the proximal orifice is referred to herein as the invivo orifice and the distal orifice is referred to as the ex vivoorifice. Preferably, at least the distal orifice is configured to couplewith a fluid flow device (or a component thereof), such as but notlimited to a connector or coupler, a valve, IV tubing, a pump, and thelike. For example, in an embodiment wherein the multi-sensor apparatusis a catheter, the distal orifice (e.g., the ex vivo orifice) isconfigured to couple to IV tubing, various types of IV connectors, andthe like. In some embodiments, both the proximal and distal orifices areconfigured to couple with IV equipment. For example, in an embodimentwherein the multi-sensor apparatus is configured as a connector (e.g., aLeur lock) the proximal orifice is configured to couple with a vascularaccess device (e.g., a catheter/cannula), IV tubing, and/or otherconnectors, and the distal end is configured to couple with a fluid flowdevice (e.g., IV tubing, a pump, etc.). Preferably; a plurality ofanalyte sensors are disposed within the lumen of the multi-sensorapparatus. For example, 2, 3, 4, 5, 6, 7, or more sensors can bedisposed within the lumen of the multi-sensor apparatus. In someembodiments, each of the plurality of analyte sensor is configured todetect a different analyte. In some embodiments, two or more of theplurality of analyte sensors are configured to detect the same analyte,thereby providing redundancy and/or fail-safes in analyte detectionand/or sensor function.

FIG. 2G provides an exemplary embodiment of a multi-sensor apparatus,namely a catheter, including an in vivo portion configured for insertioninto the host and an ex vivo portion 218 (e.g., a connector or hub)configured to remain outside the host's body afterimplantation/insertion of the in vivo portion into a host. The in vivoportion may also be referred to as the proximal portion/end of thecatheter (e.g., with respect to the host) includes an in vivo orifice ator near the catheter's tip, for fluid communication with the host'scirculatory system upon implantation into the host's vein or artery, orin an extracorporeal circulatory device. The ex vivo portion of thecatheter may also be referred to as the proximal portion (e.g., withrespect to the host). A plurality of analyte sensors 240 are disposedwithin the catheter's connector/hub, such as within the lumen/duct 254and/or within a widened portion of the catheter's in vivo portion.

FIG. 2H provides another exemplary embodiment of a multi-sensorapparatus, namely a connector, such as a Leur lock, a Y-connector, aT-connector, an X-connector, or a valve configured for connecting IVequipment. The multi-sensor apparatus includes a proximal orifice (e.g.,with respect to the host) configured to couple with a vascular accessdevice (e.g., a catheter/cannula) or with various IV equipment, such asIV tubing or another connector, and a distal orifice (e.g., with respectto the host) configured to fluidly couple to other IV equipment, asdescribed herein and is known to one skilled in the art. The analytesensors 240 are disposed within the multi-sensor apparatus's lumen orduct 254.

In various embodiments, the analyte sensors (of the multi-sensorapparatus) can be configured to detect an analyte using any means knownin the art, such as but not limited to by enzymatic, chemical, physical,electrochemical, spectrophotometric, polarimetric, calorimetric,radiometric, or immunochemical techniques, or by a combination of thesetechniques. Further more, each sensor can use a different detectiontechnique. For example, a first analyte sensor can detect a firstanalyte using a first technique, a second analyte sensor can detect asecond analyte using a second technique, a third analyte sensor candetect a third analyte using a third technique, and so on. Additionally,in some embodiments, a detection technique can be used by more than oneof the analyte sensors, wherein the technique is modified to detect aparticular analyte of interest by each of the sensors. For example, afirst sensor can be configured to detect glucose enzymatically, and asecond sensor can be configured to detect cholesterol enzymatically. Insome embodiments, one of the plurality of sensors is configured todetect an analyte optically, as described elsewhere herein.Additionally, in some embodiments, two or more of the sensors areconfigured to detect the same analyte, either by the same or differentdetection techniques.

FIGS. 2I through 2L are cross-sections of the multi-sensor apparatus ofFIGS. 2G and 2H taken along line 2I-2I, looking towards the proximalends (e.g., 212 b/258) of the devices. A plurality of analyte sensors240 is located at the luminal surface of wall 260 (e.g., the interiorsurface of the hub/connector). In some embodiments, one or more of theplurality of sensors is integrally formed with the multi-sensorapparatus. In some embodiments, the multi-sensor apparatus includes aplurality of sensor sites 262, wherein each sensor site 262 isconfigured to receive a sensor. In some embodiments, at least one of theplurality of sensor sites 262 comprises a breakaway portion (or a plug)configured for insertion therethrough of a sensor, such that at least aportion of the sensor is disposed within the lumen. One or more of thebreakaway portions can be removed, such a by punching them out, to forma channel through the wall 260. In some embodiments, the multi-sensorapparatus is manufactured such that one or more of the sensor sitesincludes a channel (e.g., through the wall), such that a sensor can beinserted there through. The sensor(s) can be installed by insertionthrough the channel(s). An adhesive, press-fit, clip or other attachmentmeans can be use to secure the sensor(s) in place. In some embodiments,a portion of a sensor 240 (e.g., the sensing portion) inserted throughthe wall 260 is disposed at the surface of the duct/lumen. In someembodiments, the portion of the sensor protrudes into the duct/lumen254. In some further embodiments, at least another portion of the sensoris disposed at the external surface of the connector/hub. In someembodiments, one or more sensors can be disposed (e.g., installed)within the duct/lumen by adhering the sensor at the surface of theduct/lumen. In some embodiments, one or more of the sensors is depositedat the surface of the duct/lumen using known analyte sensor depositiontechniques. In some embodiments, conductive traces, leads or wires canbe applied/installed, such that the sensor(s) can be connected to deviceelectronics, as is understood by one skilled in the art. For example,the device shown in FIGS. 1A and 1B include a conductive lead 24, forconnecting the analyte sensor to electronics.

Referring again to FIG. 2G, in some embodiments, the multi-sensorapparatus is a vascular access device comprising an in vivo portion andan ex vivo portion. In some preferred embodiments, the plurality ofanalyte sensors are disposed only within the ex vivo portion of thedevice, and thus do not extend into the in vivo portion (e.g., catheter212). In this embodiment, the plurality of sensors does not extendbeyond a plain defined by the host's skin. In some embodiments, the invivo portion of the multi-sensor apparatus includes a widened portion,such as a portion adjacent to and/or near to the hub, and one or more ofthe plurality of sensors are disposed within the widened portion. Insome embodiments, one or more of the analyte sensor can be configured toextend into the in vivo portion, and in some embodiments to extend intothe host's circulatory system.

Referring again to FIG. 2H, in some embodiments, the multi-sensorapparatus is a connector configured to be disposed outside the host'sbody. Accordingly, the multi-sensor apparatus does not include an invivo portion. In this embodiment, the multi-sensor apparatus isconfigured to fluidly couple to a vascular access device at its proximalend and to a flow control device at its distal end, such that the flowcontrol device can meter the flow of a non-bodily fluid (e.g., saline, aglucose solution, etc.) through the device and into the host, as well aswithdrawal of blood samples from the host (e.g., such that the sample(s)contact the analyte sensor(s)) and (optionally) reinfusion of the bloodsamples to the host. The multi-sensor apparatus of this embodimentincludes a lumen and/or duct, in which the plurality of analyte sensorsis disposed. In some embodiments, at least one of the plurality ofanalyte sensors is configured to extend into the lumen of a fluidlycoupled catheter; and in some further embodiments to extend through thecatheter and into the host's circulatory system.

In preferred embodiments, at least one of the plurality of sensors (ofthe multi-sensor apparatus) is configured to generate a signalassociated with a concentration of an analyte in a sample of the host'scirculatory system. More preferably, each of the analyte sensorsgenerates a signal associated with a concentration of each sensor'srespective analyte in the blood sample withdrawn from the host. In someembodiments, the sensors can be configured to generate signalsassociated with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more analytes and/orproperties of the sample of the host's circulatory system. In someembodiments, two or more of the sensors are configured to detect thesame analyte, such as to provide system redundancy and/or fail-safes.The analyte sensors can be configured to detect a wide variety ofanalytes, such as but not limited to glucose, oxygen, CO₂ (carbondioxide, bicarbonate), pH, creatinine, urea (nitrogen), bilirubin,electrolytes (e.g., sodium, potassium, chloride, phosphorous,magnesium), albumin, total protein, liver enzymes (e.g., alkalinephosphatase, alanine amino transferase, aspartate amino transferase),antibodies against infective agents, fibrinogen, fibronectin, lipids,triglycerides, cholesterol-protein complexes and ratios thereof (e.g.,LDL, HDL, chylomycrons), hormones (e.g., T3, T4, TSH, hGH, interleukins,etc.), medicaments, metabolites, and the like. A more extensive list ofanalytes can be found in the “Definitions” section. In some embodiments,at least one of the plurality of sensors is configured to generate asignal associated with a property of a sample of the host's circulatorysystem. Blood properties include but are not limited to pH, temperature,oxygen tension, hematocrit, viscosity, clotting, pressure, and the like.

The multi-sensor apparatus of the preferred embodiments can bemanufactured using a variety of techniques known in the art. Forexample, in some embodiments, the analyte sensors are integrally formedwith the multi-sensor apparatus. In some embodiments, at least one ofthe pluralities of sensors is deposited within the lumen of themulti-sensor apparatus, such as in the lumen/duct of the connector ofthe hub of the device illustrated in FIG. 2G, or in the lumen/duct ofthe device of FIG. 2H. In some embodiments, one or more of the analytesensors is configured to extend out of the connector/hub. For example,in the exemplary embodiment illustrated in FIG. 2G one or more analytesensors 240 can be configured to extend into and/or through the lumen212 a of the catheter 212. In another example, in the exemplaryembodiment illustrated in FIG. 2H one or more analyte sensors 240 can beconfigured to extend out of the proximal end of the multi-sensorapparatus, such that the sensor(s) can be inserted into and/or through avascular access device.

In some embodiments, the non-sensor portion of a multi-sensor apparatusis formed, and then the plurality of sensors are applied/installed. Insome embodiments, at least one of the pluralities of sensors isdeposited within the lumen, such as by screen printing. In someembodiments, at least one of the pluralities of sensors is applied tothe interior surface of the lumen, such as via an adhesive.

Alternatively, the multi-sensor apparatus may be formed about theplurality of analyte sensors, such as by using injection molding. Forexample, a mold is prepared, including sites for the analyte sensors(e.g., these will be “sensor sites,” as described elsewhere herein, whenthe manufacture process is complete). Prior to injection molding, thesensors (e.g., previously manufactured) are placed in the sites. Themold is closed and a material, such as but not limited to, e.g., moltenplastic, is injected into the mold. The material fills all of the spaceswithin the mold, including flowing around portions of the analytesensors, such that when the mold is cooled, the analyte sensors will beheld in place by the wall of the multi-sensor apparatus. For example,one or more of the sensors pass through the wall of the multi-sensorapparatus. In another example, the sensor can be oriented such that whenthe injection molding process is completed, the analyte sensor isdisposed on the surface of the lumen. In some embodiments, one or moreof the analyte sensors can be installed in the multi-sensor apparatusduring injection molding, followed by application of one or moreadditional sensors to the lumen of the device. Alternatively, the bodyof the multi-sensor apparatus, such as a fluid coupler, can be formed asmating injection-molded portions/pieces that mate together about sensorsplaced in sensor receiving sites (e.g., see FIGS. 2O-2P). A detaileddescription of this manufacturing process can be found in the sectionentitled “Exemplary Sensor Configurations.” In still other embodiments,the multi-sensor apparatuses can be formed as shown in FIGS. 2Q-2S, asdescribed elsewhere herein, by inserting whole sensors in place ofindividual electrodes, for example.

As a non-limiting example, a method for making a multi-sensor apparatusfor the detection of a plurality of analytes in a circulatory system ofa host in vivo is provided, in some embodiments. In some embodiments, aplurality of sensors is first provided. The sensors can be configured todetect one or more analytes using a variety of detection means known toone skilled in the art. Next, a multi-sensor apparatus is formed aboutthe plurality of sensors. The multi-sensor apparatus formed includes alumen, an external surface, and at least one orifice configured forcoupling with a fluid flow device, as described herein.

As another non-limiting example, in some embodiments, a method formaking a multi-sensor apparatus for the detection of a plurality ofanalytes in a circulatory of a host in vivo includes providing amulti-sensor apparatus comprising a lumen, an external surface, and atleast one orifice configured for coupling with a fluid flow device aplurality of sensors; followed by forming a plurality of sensor withinand/or on the multi-sensor apparatus.

As yet another non-limiting example, a method for detecting of aplurality of analytes in a circulatory of a host in vivo using amulti-sensor apparatus of the preferred embodiments, is provided.Accordingly, a multi-sensor apparatus of the preferred embodiments isapplied to the circulatory system of a host. As described elsewhereherein, the multi-sensor apparatus includes a lumen and a plurality ofsensors, wherein the at least two sensor are disposed above a planedefined by the skin of the host when the multi-sensor apparatus isapplied to the host's circulatory system. For example, in someembodiments, the multi-sensor apparatus is a catheter with sensors inthe hub/connector, which is inserted/implanted into a host'sartery/vein. After the catheter has been inserted/implanted into thehost, at least two of the sensors remain disposed outside the host'sbody, as defined by the host's skin. As another example, in someembodiments, the multi-sensor apparatus is a connector with sensorswithin its lumen. In this embodiment, the multi-sensor apparatus must befluidly coupled to a vascular access device, so that blood can bewithdrawn from the host's artery/vein and then contact the sensorswithin the connector. Thus, at least two of the sensors within thisembodiment of the multi-sensor apparatus remain disposed outside thehost's body, as defined by the host's skin.

Next, a sample (e.g., blood) is withdrawn from the host's circulatorysystem. When the sample is withdrawn, it is then contacted with theplurality of sensors. Each of the sensors then generates a signal. Asdescribed elsewhere herein, each sensor is configured to detect ananalyte. Accordingly, the signal generated by each sensor is associatedwith the analyte that sensor was configured to detect. The sensors canbe configured to generate the signal using any method know in the art,such as but not limited to electrochemically generating the signal,optically generating the signal, radiochemically generating the signal,physically generating the signal, chemically generating the signal,immunochemically generating the signal, and/or enzymatically generatinga signal, or combinations thereof.

In some embodiments, a withdrawn sample is reinfused into the host. Forexample, a flow control device can meter the flow of an infusion fluidinto the host, and the infusion fluid pushes the withdrawn sample backinto the host. In some embodiments, the device is configured to disposeof the withdrawn sample, such as by directing the sample to a wastecontainer.

As described herein, in some embodiments, an infusion fluid is meteredthrough the multi-sensor apparatus, and infused into the host. In someembodiments, the plurality of sensors is washed with the infusion fluid.For example, infusion of about 0.5, 1, 5, 10, 15 ml or more of infusionfluid into the host can effectively wash a previous blood sample off ofthe plurality of analyte sensor in some embodiments. A variety ofinfusion fluids can be used, including but not limited to saline,reference fluids, medicaments, parenteral nutrition fluids, hydrationfluid and the like.

In preferred embodiments, the signal of at least one of the plurality ofsensors can be calibrated. A variety of calibration methods can be used.In some embodiments, one or more of the analyte sensors can becalibrated using one or more reference data points provided by a deviceseparate from the multi-sensor apparatus/system. For example, ahand-held glucose meter can be used to provide one or more data pointsfor calibrating a glucose sensor disposed in the multi-sensor apparatus.In some embodiments, a substantially stable and/or constant analytefound in the host's blood can be used to calibrate one or more of theplurality of analyte sensors. In some embodiments, data from a recentlydisconnected multi-sensor apparatus can be used to calibrate one or moreof the sensors of a newly installed/applied multi-sensor apparatus. Insome embodiments, one of the pluralities of analyte sensors can be usedto calibrate one or more of the other sensors. In some embodiments, oneor more of the sensors can be calibrated by the manufacturer. Additionalmethods of calibration that can be used with the multi-sensor apparatusof the preferred embodiments are described elsewhere herein.

Noise

Generally, implantable sensors measure a signal (e.g., counts) relatedto an analyte of interest in a host. For example, an electrochemicalsensor can measure glucose, creatinine, or urea in a host, such as ananimal, especially a human. Generally, the signal is convertedmathematically to a numeric value indicative of analyte status, such asanalyte concentration. However, it is not unusual for a sensor toexperience a certain level of noise. The term “noise” generally refersto a signal detected by the sensor that is substantially non-analyterelated (e.g., non-glucose related). In other words, things other thanthe analyte concentration substantially cause noise. Noise is clinicallyimportant because it can reduce sensor performance, such as by makingthe analyte concentration appear higher or lower than the actualconcentration. For example, if a host is hyperglycemic (e.g., bloodsugar too high, greater than ˜120 mg/dl) or euglycemic (e.g., ˜80-120mg/dl), noise can cause the host's blood sugar to appear higher than ittruly is, which can lead to improper treatment decisions, such as togive the host an excessive insulin dose. An excessive insulin dose, insome circumstances, can lead to a dangerous hypoglycemic state (e.g.,blood sugar too low, less than ˜80 mg/dl). In the case of a hypoglycemichost, noise can cause the hosts blood sugar to appear euglycemic or evenhyperglycemic, which can also lead to improper treatment decisions, suchas not eating when necessary or taking insulin, for example.Accordingly, since noise can cause error and reduce sensor performance,noise reduction is desirable.

Noise is comprised of two components, constant noise and non-constantnoise, and can be caused by a variety of factors, ranging frommechanical factors to biological factors. For example, it is known thatmacro- or micro-motion, ischemia, pH changes, temperature changes,pressure, stress, or even unknown mechanical, electrical, and/orbiochemical sources can cause noise. In general, “constant noise”(sometimes referred to as constant background or baseline) is caused byfactors that are relatively stable over time, including but not limitedto electroactive species that arise from generally constant (e.g.,daily) metabolic processes. In contrast, “non-constant noise” (sometimesreferred to as non-constant background) is caused by transient events,such as during wound healing or in response to an illness, or due toingestion (e.g., some drugs). In particular, noise can be caused by avariety of interfering species (constant or non-constant). Interferingspecies can be compounds, such as drugs that have been administered tothe host, or products of various host metabolic processes. Exemplaryinterferents include but are not limited to a variety of drugs (e.g.,acetaminophen), H₂O₂ from exterior sources, reactive metabolic species(e.g., reactive oxygen and nitrogen species, some hormones, etc.). Insome circumstances, constant noise-causing factors can have an affect onthe sensor signal similar to non-constant noise-causing factors, such aswhen the concentration of a constant noise-causing factor temporarilyincreases, such as due to temporary lack of lymph flow (see discussionof intermittent sedentary noise).

Noise can be difficult to remove from the sensor signal by calibrationusing standard calibration equations (e.g., because the background ofthe signal does not remain constant). Noise can significantly adverselyaffect the accuracy of the calibration of the analyte signal.Additionally noise, as described herein, can occur in the signal ofconventional sensors with electrode configurations that are notparticularly designed to measure noise substantially equally at bothactive and in-active electrodes (e.g., wherein the electrodes are spacedand/or non symmetrical, noise may not be equally measured and thereforenot easily removed using conventional dual-electrode designs).

Noise can be recognized and/or analyzed in a variety of ways. Inpreferred embodiments, the sensor data stream is monitored, signalartifacts are detected and data processing is based at least in part onwhether or not a signal artifact has been detected, such as described inU.S. Patent Publication No. US-2005-0043598-A1. Additional descriptioncan also be found in U.S. Patent Publication No. US-2007-0032706-A1,both herein incorporated by reference in their entirety.

Reduction of Noise

Noise can be recognized and substantially reduced and/or eliminated by avariety of sensor configurations and/or methods, such as by using 1)sensor configurations that block and/or remove the interferent, or thatspecifically detect the noise and 2) mathematical algorithms thatrecognize and/or remove the signal noise component. The preferredembodiments provide devices and methods for reducing and/or eliminatingnoise, such as by blocking interferent passage to the sensor'selectroactive surfaces, diluting and/or removing interferents around thesensor and mathematically determining and eliminating the noise signalcomponent. Those knowledgeable in the art will recognize that thevarious sensor structures (e.g., multiple working electrodes, membraneinterference domains, etc.), bioactive agents, algorithms and the likedisclosed herein can be employed in a plurality of combinations,depending upon the desired effect and the noise reduction strategyselected. In preferred embodiments, the sensor comprises at least twoworking electrodes (one with and one without enzyme over itselectroactive surface) and an interference domain configured tosubstantially block interferent passage therethrough, such that at leastsome interferent no longer has a substantial affect on sensormeasurements (e.g., at either working electrode). The term “interferencedomain,” as used herein is a broad term, and is to be given its ordinaryand customary meaning to a person of ordinary skill in the art (and itis not to be limited to a special or customized meaning), and referswithout limitation to any mechanism of the membrane system configured toreduce any kind of noise or interferants, such as constant and/ornon-constant noise. “Noise-reducing mechanisms” as used herein is abroad term, and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and it is not to be limited to aspecial or customized meaning), and refers without limitation to anysensor system component configuration that reduces and/or eliminatesnoise on the sensor signal. Such structural configurations include butare not limited to electrode configurations (e.g., two or more workingelectrodes), membrane configurations (e.g., interference domain),algorithmic configurations (e.g., signal processing to remove anidentified noise component of the signal), and the like. In someembodiments, the interference domain is a component of the membranesystem, such as shown in FIG. 3C. However, the interference domain canbe disposed at any level (e.g., layer or domain) of the membrane system(e.g., more proximal or more distal to the electroactive surfaces thanas shown in FIG. 3C). In some other embodiments, the interference domainis combined with an additional membrane domain, such as the resistancedomain or the enzyme domain.

In another aspect, the sensor is configured to reduce noise, includingnon-constant non-analyte related noise with an overlapping measuringpotential with the analyte. A variety of noise can occur when a sensorhas been implanted in a host. Generally, implantable sensors measure asignal (e.g., counts) that generally comprises at least two components,the background signal (e.g., background noise) and the analyte signal.The background signal is composed substantially of signal contributiondue to factors other than glucose (e.g., interfering species,non-reaction-related hydrogen peroxide, or other electroactive specieswith an oxidation/reduction potential that overlaps with the analyte orco-analyte). The analyte signal (e.g., glucose) is composedsubstantially of signal contribution due to the analyte. Consequently,because the signal includes these two components, a calibration isperformed in order to determine the analyte (e.g., glucose)concentration by solving for the equation y=mx+b, where the value of brepresents the background of the signal.

In some circumstances, the background is comprised of both constant(e.g., baseline) and non-constant (e.g., noise) factors. Generally, itis desirable to remove the background signal, to provide a more accurateanalyte concentration to the host or health care professional.

The term “baseline” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a substantially constant signal derivedfrom certain electroactive compounds found in the human body that arerelatively constant (e.g., baseline of the host's physiology,non-analyte related). Therefore, baseline does not significantlyadversely affect the accuracy of the calibration of the analyteconcentration (e.g., baseline can be relatively constantly eliminatedusing the equation y=mx+b).

In contrast, “noise” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a substantially intermittent signal causedby relatively non-constant factors (e.g., the presence of intermittentnoise-causing compounds that have an oxidation/reduction potential thatsubstantially overlaps the oxidation/reduction potential of the analyteor co-analyte and arise due to the host's ingestion, metabolism, woundhealing, and other mechanical, chemical and/or biochemical factors, alsonon-analyte related). Noise can be difficult to remove from the sensorsignal by calibration using standard calibration equations (e.g.,because the background of the signal does not remain constant). Noisecan significantly adversely affect the accuracy of the calibration ofthe analyte signal. Additionally noise, as described herein, can occurin the signal of conventional sensors with electrode configurations thatare not particularly designed to measure noise substantially equally atboth active and in-active electrodes (e.g., wherein the electrodes arespaced and/or non symmetrical, noise may not be equally measured andtherefore not easily removed using conventional dual-electrode designs).

There are a variety of ways noise can be recognized and/or analyzed. Inpreferred embodiments, the sensor data stream is monitored, signalartifacts are detected, and data processing is based at least in part onwhether or not a signal artifact has been detected, such as described inU.S. Patent Publication No. US-2005-0043598-A1 and U.S. PatentPublication No. US-2007-0027370-A1, herein incorporated by reference intheir entirety.

Accordingly, if a sensor is designed such that the signal contributiondue to baseline and noise can be removed, then more accurate analyteconcentration data can be provided to the host or a healthcareprofessional.

One embodiment provides an analyte sensor (e.g., glucose sensor)configured for insertion into a host for measuring an analyte (e.g.,glucose) in the host. The sensor includes a first working electrodedisposed beneath an active enzymatic portion of a membrane on thesensor; a second working electrode disposed beneath an inactive- ornon-enzymatic portion of the membrane on the sensor; and electronicsoperably connected to the first and second working electrode andconfigured to process the first and second signals to generate ananalyte (e.g., glucose) concentration substantially without signalcontribution due to non-glucose related noise artifacts.

In one embodiment, the sensor is configured to substantially eliminate(e.g., subtract out) noise due to mechanical factors. Mechanical factorsinclude macro-motion of the sensor, micro-motion of the sensor, pressureon the sensor, local tissue stress, and the like. Since both workingelectrodes are constructed substantially symmetrically and identically,and due to the sensor's small size, the working electrodes aresubstantially equally affected by mechanical factors impinging upon thesensor. For example, if a build-up of noise-causing compounds occurs(e.g., due to the host pressing upon and manipulating (e.g., fiddlingwith) the sensor, for example) both working electrodes will measure theresulting noise to substantially the same extend, while only one workingelectrode (the first working electrode, for example) will also measuresignal due to the analyte concentration in the host's body. The sensorthen calculates the analyte signal (e.g., glucose-only signal) byremoving the noise that was measured by the second working electrodefrom the total signal that was measured by the first working electrode.

Non-analyte related noise can also be caused by biochemical and/orchemical factors (e.g., compounds with electroactive acidic, amine orsulfhydryl groups, urea, lactic acid, phosphates, citrates, peroxides,amino acids (e.g., L-arginine), amino acid precursors or break-downproducts, nitric oxide (NO), NO-donors, NO-precursors or otherelectroactive species or metabolites produced during cell metabolismand/or wound healing). As with noise due to mechanical factors, noisedue to biochemical/chemical factors will impinge upon the two workingelectrodes of the preferred embodiments (e.g., with and without activeGOx) about the same extent, because of the sensor's small size andsymmetrical configuration. Accordingly, the sensor electronics can usethese data to calculate the glucose-only signal, as described elsewhereherein.

In one exemplary embodiment, the analyte sensor is a glucose sensor thatmeasures a first signal associated with both glucose and non-glucoserelated electroactive compounds having a first oxidation/reductionpotential. For example, the oxidation/reduction potential of thenon-glucose related electroactive compounds substantially overlaps withthe oxidation/reduction potential of H₂O₂, which is produced accordingto the reaction of glucose with GOx and subsequently transfers electronsto the first working electrode (e.g., E1; FIG. 3F). The glucose sensoralso measures a second signal, which is associated with background noiseof the glucose sensor. The background noise is composed of signalcontribution due to noise-causing compounds (e.g., interferents),non-reaction-related hydrogen peroxide, or other electroactive specieswith an oxidation/reduction potential that substantially overlaps withthe oxidation/reduction potential of H₂O₂ (the co-analyte). The firstand second working electrodes integrally form at least a portion of thesensor, such as but not limited to the in vivo portion of the sensor, asdiscussed elsewhere herein. Furthermore, the sensor has a diffusionbarrier that substantially blocks (e.g., attenuates) diffusion ofglucose or H₂O₂ between the first and second working electrodes. Invarious embodiments, the sensor includes a diffusion barrier configuredto be physical, spatial, and/or temporal.

FIG. 3F is a schematic illustrating one embodiment of a sensor (e.g., aportion of the in vivo portion of the sensor, such as but not limited tothe sensor electroactive surfaces) having one or more components thatact as a diffusion barrier (e.g., prevent diffusion of electroactivespecies from one electrode to another). The first working electrode E1is coated with an enzyme layer 348 comprising active enzyme. Forexample, in a glucose sensor, the first working electrode E1 is coatedwith glucose oxidase enzyme (GOx). A second working electrode E2 isseparated from the first working electrode E1 by a diffusion barrier D,such as but not limited to a physical diffusion barrier (e.g., either areference electrode or a layer of non-conductive material/insulator).The diffusion barrier can also be spatial or temporal, as discussedelsewhere herein.

Glucose and oxygen diffuse into the enzyme layer 348, where they reactwith GOx, to produce gluconate and H₂O₂. At least a portion of the H₂O₂diffuses to the first working electrode E1, where it iselectrochemically oxidized to oxygen and transfers two electrons (e.g.,2e⁻) to the first working electrode E1, which results in a glucosesignal that is recorded by the sensor electronics (not shown). Theremaining H₂O₂ can diffuse to other locations in the enzyme layer or outof the enzyme layer (illustrated by the wavy arrows). Without adiffusion barrier D, a portion of the H₂O₂ can diffuse to the secondworking electrode E2, which results in an aberrant signal that can berecorded by the sensor electronics as a non-glucose related signal(e.g., background).

Preferred embodiments provide for a substantial diffusion barrier Dbetween the first and second working electrodes (E1, E2) such that theH₂O₂ cannot substantially diffuse from the first working electrode E1 tothe second working electrode E2. Accordingly, the possibility of anaberrant signal produced by H₂O₂ from the first working electrode E1 (atthe second working electrode E2) is reduced or avoided.

In some alternative embodiments, the sensor is provided with a spatialdiffusion barrier between electrodes (e.g., the working electrodes). Forexample, a spatial diffusion barrier can be created by separating thefirst and second working electrodes by a distance that is too great forthe H₂O₂ to substantially diffuse between the working electrodes. Insome embodiments, the spatial diffusion barrier is about 0.01, 0.02,0.03, 0.04, 0.05, 0.06, 0.07, or 0.08 inches to about 0.09, 0.10, 0.11,or 0.120 inches. In other embodiments, the spatial diffusion barrier isabout 0.020 inches to about 0.050 inches. Still in other embodiments,the spatial diffusion barrier is about 0.055 inches to about 0.095inches. A reference electrode R (e.g., a silver or silver/silverchloride electrode) or a non-conductive material (e.g., a polymerstructure or coating such as Parylene) can be configured to act as aspatial diffusion barrier.

In some preferred embodiment, the sensor is an indwelling sensor, suchas configured for insertion into the host's circulatory system via avein or an artery. In some exemplary embodiments, an indwelling sensorincludes at least two working electrodes that are inserted into thehost's blood stream through a catheter. The sensor includes at least areference electrode that can be disposed either with the workingelectrodes or remotely from the working electrodes. The sensor includesa spatial, a physical, or a temporal diffusion barrier. A spatialdiffusion barrier can be configured as described in U.S. PatentPublication No. US-2008-0083617-A1 which is incorporated by referenceherein in its entirety.

In one exemplary embodiment of an indwelling analyte sensor, such as butnot limited to an intravascular glucose sensor to be used from a fewhours to ten days or longer. Namely, the sensor includes two workingelectrodes. A first working electrode detects the glucose-related signal(due to active GOx applied to the electroactive surface) as well asnon-glucose related signal. The second working electrode detects onlythe non-glucose related signal (because no active GOx is applied to itselectroactive surface). H₂O₂ is produced on the first working electrode(with active GOx). If the H₂O₂ diffuses to the second working electrode(the no GOx electrode) an aberrant signal will be detected at thiselectrode, resulting in reduced sensor activity. Accordingly, it isdesirable to separate the electroactive surfaces with a diffusionbarrier, such as but not limited to a spatial diffusion barrier.Indwelling sensors are described in more detail in copending U.S. PatentPublication No. US-2008-0119703-A1, herein incorporated in its entiretyby reference.

To configure a spatial diffusion barrier between the working electrodes,the location of the active enzyme (e.g., GOx) is dependent upon theorientation of the sensor after insertion into the host's artery orvein. For example, in an embodiment configured for insertion in thehost's blood flow (e.g., in an artery or vein), active GOx and theinactive GOX (or no GOx) would be applied to two working electrodes suchthat the active GOX would be downstream from the inactive GOX (e.g.,relative to the direction of blood flow). Due to this configuration,H₂O₂ produced at plus-GOX electroactive surface would be carrier downstream (e.g., away from minus-GOX electroactive surface) and thus notaffect the non-enzymatic working electrode.

In some embodiments, a physical diffusion barrier is provided by aphysical structure, such as an electrode, insulator, and/or membrane.For example, in some embodiments, an insulator or reference electrodedisposed between the working electrodes acts as a diffusion barrier. Asanother example, the diffusion barrier can be a bioprotective membrane(e.g., a membrane that substantially resists, attenuates or blocks thetransport of a species (e.g., hydrogen peroxide), such as apolyurethane. As yet another example, the diffusion barrier can be aresistance domain, as described in more detail elsewhere herein; namely,a semipermeable membrane that controls the flux of oxygen and an analyte(e.g., glucose) to the underlying enzyme domain. Numerous otherstructures and membranes can function as a physical diffusion barrier asis appreciated by one skilled in the art.

In other embodiments, a temporal diffusion barrier is provided (e.g.,between the working electrodes). By temporal diffusion barrier is meanta period of time that substantially prevents an electroactive species(e.g., H₂O₂) from diffusing from a first working electrode to a secondworking electrode. For example, in some embodiments, the differentialmeasurement can be obtained by switching the bias potential of eachelectrode between the measurement potential and a non-measurementpotential. The bias potentials can be held at each respective setting(e.g., high and low bias settings) for as short as milliseconds to aslong as minutes or hours. Pulsed amperometric detection (PED) is onemethod for quickly switching voltages, such as described in Bisenberger,M.; Brauchle, C.; Hampp, N. A triple-step potential waveform at enzymemultisensors with thick-film gold electrodes for detection of glucoseand sucrose. Sensors and Actuators 1995, B. 181-189, which isincorporated herein by reference in its entirety. In some embodiments,bias potential settings are held long enough to allow equilibration.

One preferred embodiment provides a glucose sensor configured forinsertion into a host for measuring glucose in the host. The sensorincludes first and second working electrodes and an insulator locatedbetween the first and second working electrodes. The first workingelectrode is disposed beneath an active enzymatic portion of a membraneon the sensor and the second working electrode is disposed beneath aninactive- or non-enzymatic portion of the membrane on the sensor. Thesensor also includes a diffusion barrier configured to substantiallyblock (e.g., attenuate, restrict, suppress) diffusion of glucose orhydrogen peroxide between the first and second working electrodes.

In a further embodiment, the glucose sensor includes a referenceelectrode configured integrally with the first and second workingelectrodes. In some embodiments, the reference electrode can be locatedremotely from the sensor, as described elsewhere herein. In someembodiments, the surface area of the reference electrode is at least sixtimes the surface area of the working electrodes. In some embodiments,the sensor includes a counter electrode that is integral to the sensoror is located remote from the sensor, as described elsewhere herein.

In a further embodiment, the glucose sensor detects a first signalassociated with glucose and non-glucose related electroactive compoundshaving a first oxidation/reduction potential (e.g., theoxidation/reduction potential of H₂O₂). In some embodiments, the glucosesensor also detects a second signal is associated with background noiseof the glucose sensor comprising signal contribution due to interferingspecies, non-reaction-related hydrogen peroxide, or other electroactivespecies with an oxidation/reduction potential that substantiallyoverlaps with the oxidation/reduction potential of hydrogen peroxide;the first and second working electrodes integrally form at least aportion of the sensor; and each of the first working electrode, thesecond working electrode and the non-conductive material/insulator areconfigured provide at least two functions such as but not limited toelectrical conductance, insulation, structural support, and a diffusionbarrier

In further embodiments, the glucose sensor includes electronics operablyconnected to the first and second working electrodes. The electronicsare configured to calculate at least one analyte sensor data point usingthe first and second signals described above. In still another furtherembodiment, the electronics are operably connected to the first andsecond working electrode and are configured to process the first andsecond signals to generate a glucose concentration substantially withoutsignal contribution due to non-glucose noise artifacts.

Sensor Configurations for Equivalent Measurement of Noise Signals at theTwo Working Electrodes

In dual-electrode biosensors (e.g., an analyte sensor having two workingelectrodes E1, E2), noise can be caused by a variety of sources, forexample, located outside (e.g., by noise-causing species producedmetabolically and/or consumed by the host) or within (e.g., crosstalk)the sensor. In some circumstances, biological and/or metabolic processesoccurring in the host's body, such as in the locale of the implantedsensor, can cause noise. These metabolic processes, such as but notlimited to wound healing, the body's response to illness and even dailycellular metabolic processes, can generate noise-causing metabolicspecies (e.g., compounds, substances) that impinge upon the sensor andcause noise on the signal. For example, some noise-causing species, thelevels of which are relatively stable due to production during dailycellular metabolism, generally cause constant noise. In another example,some noise-causing species, the levels of which fluctuate due toproduction by intermittent metabolic process (e.g., wound healing orresponse to infection), generally cause non-constant noise.Noise-causing metabolic species include but are not limited toexternally generated H₂O₂ (e.g., produced outside the sensor), compoundshaving electroactive acidic, amine or sulfhydryl groups, urea, lacticacid, phosphates, citrates, peroxides, amino acids (e.g. L-arginine),amino acid precursors or break-down products, nitric oxide (NO),NO-donors, NO-precursors, reactive oxygen species or other electroactivespecies or metabolites produced during cell metabolism and/or woundhealing, for example. Noise-causing species, such as drugs, vitamins andthe like, can also be consumed by the host. These noise causing speciesinclude but are not limited to acetaminophen, ascorbic acid, dopamine,ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline,tolazamide, tolbutamide and triglycerides. Further discussion of noiseand its sources can be found in U.S. Patent Publication No.US-2007-0027370-A1 and U.S. Patent Publication No. US-2007-0235331-A1,both of which are incorporated herein by reference in their entirety.

In dual-electrode sensors, noise can also be generated within thesensor, namely due to diffusion of a measured species (e.g., H₂O₂) froma first working electrode (e.g., the H₂O₂ is generated in an activeenzymatic portion of the sensor membrane associated with the firstworking electrode) to a second working electrode and detection thereby(e.g., which is associated with a non-enzymatic portion of the sensormembrane). This type of noise is commonly referred to as “crosstalk.”Crosstalk is undesirable as it causes sensor error, which can result ininaccurate reporting of sensor data. In conventional sensors, a commonsolution to the problem of crosstalk is to space the two workingelectrodes far enough apart that a measured species diffusing from oneworking electrode cannot reach the other working electrode;unfortunately, such spacing does not enable substantially equivalentmeasurement of noise-cause species, as discussed in more detailelsewhere herein. Unlike conventional sensors, the sensors of thepreferred embodiments ensure accurate subtraction of noise signal byensuring substantially equivalent measurement of the noise (e.g., noisecomponent, constant and/or non-constant noise components) detected bythe two working electrodes.

Depending upon the scale (e.g., point) of reference, noise has a dualnature. On a larger scale, with respect to the in vivo portion of thesensor and the surrounding tissue, noise occurs randomly (e.g., isscattered, intermittent, dispersed, unevenly distributed) in the localof an implanted sensor. Yet, on a smaller scale, such as that of a fewcells (e.g., 100-300 microns), noise is a localized phenomenon becauseit creates hot spots of noise-causing species generation whose effectsextend about a thousandths of an inch (e.g., localized nature,character). A “hot spot” of noise generation is referred to herein as a“point source.” A point source (e.g., a localized hot spot for noisegeneration) can be a cell or a group of cells adjacent to the sensormembrane, or a noise-causing species (e.g., compound, substance,molecule) that diffused to the location of sensor implantation, such asby diffusion between cells (e.g., to the sensor). For example, in thecircumstance of a single point source in contact with the sensormembrane's surface, noise is a local phenomenon, because thenoise-causing species' ability to affect adjacent structures is limitedby the maximum distance it can diffuse (e.g., through the membrane),which is generally very short (e.g., a few microns, such as betweenabout 1-μm to about 500-μm). Due to the random yet localized nature ofnoise, the configuration of the electroactive surfaces (of the workingelectrodes) can substantially affect noise measurement. With respect tothe configuration and arrangement (e.g., surface area) of thedual-electrode sensor's electroactive surfaces, the random yet localizednature of noise is discussed in greater detail below.

FIG. 3G is a two-dimensional schematic illustrating, on the scale of asensor and the surrounding tissue (e.g., a generally larger scale), therandom nature of noise relative to a dual-electrode sensor, in oneexemplary embodiment. This figure is for illustrative purposes only, andshould not be considered as a to-scale representation of a particularsensor configuration or of the events discussed herein. In theembodiment shown in FIG. 3G, the dual-electrode analyte sensor includestwo electroactive surfaces E1, E2 disposed beneath the sensor'smembrane. While FIG. 3G illustrates only one dimension of theelectroactive surfaces, in some embodiments, the electroactive surfaces(e.g., the surface area of each electroactive surface) can include botha length and a width. In some embodiments, the area can includeadditional dimensions, such as a circumference and/or a height. In someembodiments, the sensor can have a planar configuration. In someembodiments, the sensor can have a cylindrical, pyramidal, polygonalconfiguration. It should also be understood that the electroactivesurfaces E1, E2 are shown as boxes as a matter of illustrativeconvenience; however, electroactive surfaces can be thinner or thickerthan illustrated in FIG. 3G or elsewhere herein. The membrane has athickness D1 and a surface MS. Depending upon the membraneconfiguration, fabrication methods and/or materials, D1 can vary insize, from less than about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006,0.007, 0.008, 0.009, or 0.010 inches to more than about 0.011, 0.012,0.013, 0.014, 0.015, 0.015, 0.016, 0.017, 0.018, 0.019, 0.020, 0.025,0.03, 0.035, or 0.050 inches. In some embodiments, a preferred membranethickness is between about 0.001, 0.0012, 0.0014, 0.0016, or 0.0018inches to about 0.002, 0.0022, 0.0024, 0.0026, 0.0028, or 0.003 inches.Noise-causing species (represented by squiggly arrows N2) can begenerated by and/or at point sources N1 (e.g., noise hot spots) unevenlydistributed relative the in vivo portion of the sensor. For example,some of the point sources N1 (shown in FIG. 3G) are concentrated at oneend of electroactive surface E1, while some are distributed more evenlyacross electroactive surface E2. In some circumstances, the point sourcemay be one or more cells (e.g., in contact with the membrane surface MS)that release the noise-causing species during wound healing or anothermetabolic process, such as when a sensor is implanted in vivo. In somecircumstances, the implanted sensor can be located within the diffusiondistance of one or more noise-causing species produced during a nearbymetabolic process. In some circumstances, the noise-causing species(e.g., a compound consumed by the host) can be carried to the local ofthe sensor via the circulatory and/or lymph system and diffuse to thesensor (e.g., between cells).

Random and/or unequally distributed noise can be generated in a varietyof circumstances. For example, a peroxide-generating immune cell couldbe located adjacent to one electroactive surface but not the other. Ingeneral, a noise-causing species must be generated and/or occur closeenough to the sensor membrane such that it can diffuse to (and through)the membrane, to the electroactive surfaces, and affect the sensorsignal. If the noise-causing species is generated farther away from themembrane than the diffusion distance of the noise-causing species, thenthe noise-causing species may be unable to reach the electroactivesurfaces, and therefore may have little effect on sensor signal. Forexample, H₂O₂ (produced by metabolic process when the sensor isimplanted in a host) must be generated sufficiently close to themembrane for it to diffuse to the membrane and affect sensor function.The maximum distance that the noise-causing species can diffuse (e.g.,from the cell to the membrane, from one working electrode to anotherworking electrode) and still substantially affect sensor function isreferred to herein as a “diffusion distance.”

The sensor electronics are configured to mathematically correct fornoise on the sensor signal (e.g., such as by subtraction of the noisesignal, applying a filter, averaging, or other calculations), such thata substantially analyte-only signal can be presented to the user. Theinventors have discovered that successful mathematical correction ofnoise on the sensor signal can be substantially affected by theequivalence (e.g., similarity) of the noise signals detected by the twoworking electrodes. If the detected noise signals are substantiallyequivalent (e.g., similar amounts, amplitudes, levels, relativelyequal), then the calculations will produce a more accurate resultantanalyte signal. If, on the other hand, the detected noise signals arenot substantially equal (e.g., have very different amplitudes and/orwave forms), then the calculations will have a greater degree of error.While not wishing to be bound by theory, it is believed thatpresentation of more accurate sensor data (e.g., to the host) willimprove the host's management of his or her diabetes, which will preventthe immediate risks of hypoglycemia (e.g., loss of consciousness anddeath) and postpone and/or prevent long term diabetes complications(blindness, loss of limb, kidney dysfunction, and the like).Additionally, the increased accuracy afforded by the sensors of thepreferred embodiment increases the feasibility of insulin dosing and/oran artificial pancreas system based on a continuous glucose sensor.

In order to compensate for the unevenly distributed nature of noise(e.g., the point sources are randomly and/or non-equally and/ornon-equivalently distributed relative to the in vivo portion of thesensor) and thereby render the noise components equivalent, a continuousdual-electrode glucose sensor having sufficiently large electroactivesurfaces, such that the noise components can be substantially equalized(e.g., made and/or become equivalent) by integration there across, isprovided in one embodiment. The first working electrode includes a firstelectroactive surface (E1, FIG. 3G) disposed beneath an active enzymaticportion (e.g., plus-GOx) of the sensor's membrane, as describedelsewhere herein. The first electroactive surface includes a first area(e.g., first electroactive surface area) configured to detect a firstsignal (e.g., including an analyte-related component and a noisecomponent) having a first noise component related to a noise-causingspecies. The sensor also includes a second working electrode having asecond electroactive surface (E2, FIG. 3G) disposed beneath aninactive-enzymatic or a non-enzymatic portion of the sensor membrane, asdescribed elsewhere herein. For example, an inactive-enzymatic portionof the membrane can include inactivated GOx or no GOx. The secondelectroactive surface includes a second area (e.g., second electroactivesurface area) configured to generate a second signal having a secondnoise component related to the noise-causing species. In preferredembodiments, the first and second areas are dimensioned (e.g., sized) tobe sufficiently large such that the first and second noise componentsintegrated there across, such that the first and second integrated noisesignals (e.g., from the first and second electroactive surfaces,respectively) are substantially equivalent. In some embodiments, thefirst and second integrated noise signals (e.g., noise components) arewithin 20% of each other (e.g., plus or minus 10%). In some embodiments,the first and second electroactive surfaces are dimensioned to integratenoise caused by a plurality of local point sources that producenoise-causing species in vivo.

FIG. 3H is a two-dimensional schematic illustrating the localizedcharacter of noise species (represented by squiggly arrows N2) generatedby a point source N1, when examined from a cellular scale, as discussedelsewhere herein. FIG. 3H depicts a cross-section of a sensor, in oneembodiment, wherein the sensor includes two working electrodes havingelectroactive surfaces E1 and E2, and a membrane having surface MS andthickness D1. Distance D3 separates the electroactive surfaces; thedistance between their outer edges is denoted by D4. Note that dimensionD2, described above, is not shown in this figure. The sensor of thisexemplary embodiment can have a variety of configurations, such as butnot limited to planar, cylindrical or polygonal. Accordingly, thedimensions of an electroactive surface's surface area (referred to as“area” herein) can include but are not limited to length, width, height,and/or circumference. For example, in some embodiments, the area of eachelectroactive surface is defined by a length and a width. In someembodiments, the area includes a length or width and a circumference. Insome embodiments, the area includes length, width and height.Additionally, it is known to one skilled in the art that, in somecircumstances, differences in signal amplitude and/or sensitivity (e.g.,from the two working electrodes), due to differences in electrode sizes(or some differences in compositions of membranes) can be corrected(adjusted, compensated for, calibrated out) mathematically. For example,if a first electroactive surface is two times as large as the secondelectroactive surface, then the signal from the second electroactivesurface can be multiplied by two, such that the sensitivities aresubstantially similar.

Referring now to FIG. 3H, in this exemplary circumstance the pointsource (e.g., noise hot spot) is an individual cell N1 disposed adjacentto the membrane surface MS and generally above and/or over the sensor'selectroactive surfaces E1, E2. The cell can produce noise-causingsubstances (e.g., N2) that can diffuse to and affect its localenvironment. In general, the ability of a noise-causing substance toaffect the local environment is limited by the maximum distance thesubstance can diffuse (e.g., the substance's diffusion distance). Insome circumstances, some of the noise-causing substances can diffusethrough the sensor membrane and affect the sensor's electroactivesurfaces. While not wishing to be bound by theory, the inventors havefound that in order for the two electroactive surfaces to besubstantially equivalently affected by the noise N2 from a point source,such as a cell, the electroactive surfaces must be affected bysubstantially the same microenvironment. In various circumstances, theelectroactive surfaces will be affected by substantially the samemicroenvironment, if the electroactive surfaces are configured andarranged such that the electroactive surfaces are sufficiently closetogether and/or their external edges are sufficiently close together.

FIG. 3H shows that the sensor's electroactive surfaces E1, E2 areseparated by a distance D3 and their outer edges are spaced a distanceD4 (e.g., in at least one dimension), in one exemplary embodiment. Inthis example, a point source N1 (e.g., a cell) of noise-causing species1006 is adjacent to the membrane's surface MS. If the electroactivesurfaces are configured and arranged such that D3 is sufficiently small,then the noise-causing species diffusing from the point source canimpinge equivalently on both of the electroactive surfaces. Additionallyor alternatively, if D4 is sufficiently small (e.g., the electroactivesurfaces are sufficiently narrow in at least one dimension), then thenoise-causing species diffusing from the point source can impingeequivalently on both of the electroactive surfaces. Accordingly, inpreferred embodiments, the electroactive surfaces are spaced a distance(e.g., relative to each other, D3) such that the electroactive surfaces(e.g., at least a portion of each electroactive surface) detectsubstantially equivalent noise from a point source. In some embodiments,the electroactive surfaces are sufficiently close together (e.g., suchthat the noise components measured are substantially equal) when thedistance between the electroactive surfaces (D3) is between about0.5-times to about 10-times (or more) the membrane thickness (D1). Insome preferred embodiments, the electroactive surfaces are sufficientlyclose together when D3 is about 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-timesthe membrane thickness. In some embodiments, D3 is between about 5, 10,15, 20, 25, 30, 35, 40, 45, or 50 microns or less to about 55, 60, 65,70, 75, 80, 85, 90, 95, or 100 microns or more. In preferredembodiments, D3 is between about 20 to about 40 microns. In someembodiments, D4 is between about 25 microns or less to about 500 micronsor more.

Depending upon the sensor's configuration, in some embodiments, D4 canbe the distance between the outer edges of the electroactive surfaces,or D4 can be a distance equivalent to the maximum diameter of thebundles and/or twisted pair of working electrodes. For example, FIG. 3Hillustrates a cross-section of a sensor (e.g., width and height), butdoesn't illustrate any additional dimensions (e.g., length). Thecross-section could be that of a planar sensor configuration, whereinthe sensor also includes an additional dimension that has not beenshown, such as but not limited to D2. In some circumstances, the sensorcan have a non-planar configuration. For example, in the embodimentshown in FIG. 3I, the working electrodes E1, E2 are fabricated from twowires. Since the wires are cylindrical, the electroactive surfaces donot include outer edges. In this exemplary circumstance, D4 is the totaldiameter of the bundled and/or twisted pair of working electrodes. Inboth types of sensor configurations (e.g., planar and non-planar), if D4is sufficiently small, then the two working electrodes can beequivalently affected by noise-causing species N2 derived from a pointsource N1.

As described above, dual-electrode sensors can be affected by internallygenerated noise (e.g., generated by the sensor). The inventors havefound that, in general, when D3 is sized to be sufficiently small suchthat the electroactive surfaces are equivalently affect by noise from anadjacent point source, the electroactive surfaces are also close enoughtogether that crosstalk (an internally generated noise) can occur. Ingeneral, crosstalk is detection of an analyte signal generated at theplus-GOx working electrode (wherein the electrode includes the membraneportion thereon) by the minus-GOx working electrode (including the NoGOx membrane portion thereon). For example, when the measured species isH₂O₂, crosstalk occurs when the H₂O₂ diffuses from the plus-GOx enzymedomain to the No GOx working electrode and is detected (e.g., a signalis generated on the No GOx electrode). In general, crosstalk isundesirable as it causes sensor error. However, in order for the twoworking electrodes to measure equivalent noise signals from a pointsource N1, the electroactive surfaces must be spaced very closetogether. Accordingly, in preferred embodiments, this distance (D3) isless than a crosstalk diffusion distance of the measured species. Inother words, D3 is shorter than the diffusion distance of H₂O₂ (e.g.,the maximum distance H₂O₂ can diffuse from a first electrode to a secondand still cause a signal on the second electrode).

In conventional dual-electrode sensors, spacing the electroactivesurfaces within the crosstalk diffusion distance of the measured speciesis generally undesirable due to increased sensor error. However, inpreferred embodiments, the sensor includes a physical diffusion barrierconfigured to attenuate crosstalk by physically blocking (e.g.,suppressing, blocking, restricting) some of the crosstalk from theactive enzymatic portion of the sensor membrane to the secondelectroactive surface. More preferably, the physical diffusion barrieris configured and arranged to attenuate and/or physically block asubstantial amount of the measurable species (e.g., H₂O₂) diffusing fromthe active enzymatic portion of the membrane to the second electroactivesurface, such that there is substantially no signal associated withcrosstalk measured at the second working electrode.

FIG. 3I is a schematic illustrating a perspective view of across-section of a dual-electrode sensor that includes a physicaldiffusion barrier D, in one exemplary embodiment. In this embodiment,wires form the working electrodes E1, E2. The working electrodes eachinclude a membrane, including an electrode domain 347, an enzyme domain248 and a resistance domain 249. For example, E1 includes a firstelectrode domain, a first enzyme domain (Plus GOx) and a firstresistance domain, and E2 includes a second electrode domain, a secondenzyme domain (No GOx) and a second resistance domain. In thisparticular exemplary embodiment, the electrodes are placed together andcoated with an additional resistance domain 249A (e.g., a thirdresistance domain). Depending upon the circumstances, the electrodes canbe placed and/or held together using a variety of methods, such asbundling, twisting, wrapping, and the like, either alone or incombination. The distances shown are as follows; a thickness of themembrane D1, at least one dimension of the electroactive surface D2, adistance between the electroactive surfaces D3, and a distance betweenthe outer edges of the electroactive surfaces D4. In the illustratedexemplary embodiment, the first and second electroactive surfaces extendabout the circumferences of E1 and E2 (or portions thereof),respectively.

In preferred embodiments, the physical diffusion barrier D is disposedbetween the electroactive surfaces of working electrodes E1 and E2. Insome embodiments, the physical diffusion barrier is formed of one ormore membrane materials, such as those used in formation of aninterference domain and/or a resistance domain. Such materials includebut are not limited to silicones, polyurethanes, cellulose derivatives(cellulose butyrates and cellulose acetates, and the like) andcombinations thereof, as described elsewhere herein. In someembodiments, the physical diffusion barrier includes one or moremembrane domains. For example, in the exemplary embodiment of FIG. 3I,the physical diffusion barrier is a discontinuous portion of themembrane (e.g., separate, distinct or discontinuous membrane structures)disposed between the first and second electroactive surfaces, and caninclude one or more membrane portion(s) within distance D3 (e.g.,interference and/or resistance domains). For example, in someembodiments, H₂O₂ diffusing from the Plus GOX working electrode to theNo GOx working electrode must pass through two “sensor membranes” suchas the first and second resistance domains disposed on E1 and E2respectively, and optionally electrode, interference and/or enzymedomains disposed on E2. In some embodiments, the physical diffusionbarrier includes first and second barrier layers formed independently onthe first and second electrodes. In some embodiments the barrier layeris the resistance domain 349. In still other embodiments, the physicaldiffusion barrier can be a continuous membrane (and/or membranedomain(s)) disposed between the electroactive surfaces. In someembodiments, the physical diffusion barrier attenuates (e.g.,suppresses, blocks, prevents) diffusion of the H₂O₂ (e.g., crosstalk) byat least 2-fold. In preferred embodiments, crosstalk is attenuated atleast 5-fold. In a more preferred embodiment, crosstalk is attenuated atleast 10-fold. In some embodiments, the physical diffusion barrierattenuates crosstalk at least about 50%. In a further embodiment, thephysical diffusion barrier is configured and arranged to physicallyblock an amount of the measured species diffusing from the activeenzymatic portion of the membrane to the second electroactive surface,such that there is substantially no signal associated with crosstalkmeasured at the second working electrode.

In some embodiments, a dual-electrode sensor having a physical barrierlayer can be fabricated by initially preparing (e.g., fabricating,building) the first and second working electrodes E1, E2 independently(e.g., separately from each other), followed by joining and/or groupingand/or bundling the working electrodes and optionally applying one ormore additional membrane domains fabrication. In this exemplaryembodiment, to the first working electrode E1, an optional electrodedomain 347, an enzyme domain 348 (e.g., plus-GOx), and at least onelayer of the resistance domain material 349 (e.g., first resistancedomain) are sequentially applied. Similarly, to the second workingelectrode E2, an optional electrode domain 347, an enzyme domain 348(e.g., no-GOx), and at least one layer of the resistance domain material349 (e.g., second resistance domain) are sequentially applied. Theworking electrodes are then held together, such as but not limited to bybundling and/or twisting them together, wrapping a material around them,or by any other method known in the art. In this embodiment, thephysical diffusion barrier D includes a discontinuous portion of amembrane (e.g., the initial layers of the resistance domain materialapplied independently to the two working electrodes) disposed betweenthe first and second electroactive surfaces.

In an alternative exemplary sensor embodiment, the sensor includesworking electrodes (including electroactive surfaces) disposed on aplanar substrate and/or surface. The electroactive surfaces can bespaced a distance D3 that is sufficiently close together that theelectroactive surfaces are equivalently affected by an adjacent noisehot spot (e.g., point source). In this configuration, D3 is alsosufficiently small that crosstalk can occur between the Plus GOx workingelectrode (wherein the term “electrode” includes the membrane disposedthereon, for the purposes of this example) and the No GOx workingelectrode. However, in preferred embodiments, crosstalk is substantiallyattenuated by a physical diffusion barrier disposed between the workingelectrodes. Namely, the electrode domains (if present) and enzymedomains can be separately applied to the working electrodes and/orelectroactive surfaces; followed by application of a continuousresistance domain applied thereon, such that a portion the resistancedomain is deposited between the working electrodes. For example, aportion of resistance domain deposited on a planar substrate and betweenworking electrodes can attenuate diffusion of the measured species(e.g., H₂O₂) from E1 to E2, such that the noise measured on E1 and E2 isequivalent.

In the context of glucose sensors, one skilled in the art recognizesthat equivalent noise signals can have different amplitudes, butequivalent signal patterns (e.g., rises, falls, trends and the like)such that a noise component can be subtracted out (as describedelsewhere herein) while compensating for any difference in signalamplitude (e.g., sensitivity of the first and second workingelectrodes), as described elsewhere herein. In some circumstances, themembrane portions associated with the working electrodes (e.g., of adual-electrode sensor) can possess different sensitivities (e.g., signalsensitivities), such that the amplitudes of the noise componentsmeasured by the working electrodes are not equivalent. In somecircumstances, the areas of the electroactive surfaces may be differentsizes, which can also result in non-equivalent signal amplitudes,differences in measured baselines and/or sensitivities between the firstand second working electrodes. While such differences in signal baselineand/or sensitivity can be corrected mathematically (e.g., bymathematical filters), mathematical correction of noise, in general, isimproved when the signal sensitivities of the first and second workingelectrodes are closer. Accordingly, in a preferred embodiment, anadditional resistance domain 349A (e.g., applied continuously over thediscontinuous resistance domains 349 described elsewhere herein) isprovided, such that the signal sensitivities are equivalent. In theexemplary embodiment shown in FIG. 3I, the signal sensitivities aresubstantially equalized on a sensor including the combination ofdiscontinuous resistance domains (e.g., resistance domains 349, appliedindependently to E1 and E2) and a continuous resistance domain 349A(e.g., applied over and/or adjacent to the discontinuous resistancedomains). In other words, the noise signals detected on both E1 and E2will have substantially the same amplitude (e.g., intensity, amount), asdescribed with reference to Example 7, below. In a preferred embodiment,the sensitivities (of the working electrodes) are within 40% of eachother (e.g., plus or minus 20%). In a preferred embodiment, thesensitivities (of the working electrodes) are within 20% of each other(e.g., plus or minus 10%). In a more preferred embodiment, thesensitivities (of the working electrodes) are within 10% of each other(e.g., plus or minus 5%).

In an alternative embodiment, the sensor electrodes can be disposed on aplanar, cylindrical, pyramidal or otherwise shaped support. For example,the sensor's first and second working electrodes can be conductivetraces deposited, such as by screen printing, sputtering or other thinfilm techniques known in the art, on a planar substrate. In thisalternative embodiment, a physical diffusion barrier can be formed bylayers of resistance domain material deposited separately (e.g.,discontinuously) on each working electrode and/or between theelectrodes, for example.

In the exemplary embodiments described above, diffusion of the H₂O₂ fromthe first working electrode E1 to the electroactive surface of thesecond working electrode E2 is first attenuated by the resistance domain349 disposed over the first working electrode E1 (an independentlyformed first barrier layer), and then again by the resistance domain 349disposed over the second working electrode E2 (an independently formedsecond barrier layer), such that only insubstantial amounts of H₂O₂ canreach the electroactive surface of the second working electrode. Inpreferred embodiments, the first and second resistance domains areconfigured and arranged to reduce diffusion of the measurable species(e.g., H₂O₂) from the first electroactive surface to the secondelectroactive surface by at least 2-fold. In more preferred embodiments,the physical diffusion barrier is configured and arranged to reducediffusion of the measurable species by at least 10-fold. In someembodiments, the physical diffusion barrier is configured and arrangedto reduce diffusion of the measurable species by at least 3-, 4-, 5-,6-, 7-, 8-, or 9-fold. In some embodiments, the physical diffusionbarrier is configured and arranged to reduce diffusion of the measurablespecies by at least 20-, 30-, 40- or 50-fold, or more. In someembodiments, the sensor's working electrodes E1, E2 are by an insulator,which insulates the working electrodes from each other. In someembodiments, the insulator is at least a portion of the sensor membrane.

In some embodiments, a continuous glucose sensor configured forinsertion into a host and detecting glucose in the host is provided. Ingeneral, the sensor includes first and second working electrodes,wherein each working electrode includes an electroactive surface (eachincluding an area) disposed beneath a sensor membrane. The firstelectroactive surface (e.g., of the first working electrode) is disposedbeneath an active enzymatic portion (plus-GOx) of the membrane while thesecond electroactive surface (of the second working electrode) isdisposed beneath a non-enzymatic (no-GOx) portion of the membrane. Thenon-enzymatic portion of the membrane can include inactivated enzymeand/or no enzyme. Additionally, each working electrode is configured togenerate a signal having a noise component related to a noise-causingspecies. In some circumstances, the noise-causing species isnon-constant and related to a biological process. Preferably, the firstand second areas are sufficiently large such that the noise components(e.g., first and second noise components detected by the first andsecond working electrodes) are substantially equivalent. In someembodiments, the first and second areas are each greater than the sum ofthe diameters of about 10 average human cells, in at least onedimension. In some embodiments, the first and second areas are eachgreater than about 500 μm, in at least one dimension. Preferably, thefirst and second areas (e.g., of the electroactive surfaces) areconfigured and arranged such that the signals caused by a plurality oflocal point sources (that produce noise-causing species when implantedin a host) can be integrated along each area (e.g., each areaindependently from the other). In some further embodiments, the firstand second areas are configured and arranged to integrate signalsdetected about a circumference of the sensor. Preferably, the first andsecond electroactive surfaces are spaced a distance that is less than acrosstalk diffusion distance of a measured species, such as H₂O₂produced in the active enzymatic portion of the membrane. In someembodiments, the sensor includes a physical diffusion barrier configuredand arranged to physically block some crosstalk from the activeenzymatic portion of the membrane to the second electroactive surface.In some further embodiments, the physical diffusion barrier isconfigured and arranged to physically block a substantial amount of themeasurable species diffusing from the active enzymatic portion of themembrane to the second electroactive surface (e.g., crosstalk), suchthat there is substantially no signal associated with crosstalk measuredat the second working electrode. In some embodiments, the physicaldiffusion barrier is a discontinuous portion of the membrane disposedbetween the first and second electroactive surfaces. In some furtherembodiments, the physical diffusion barrier includes a first barrierlayer formed on the first working electrode and a second barrier layerformed on the second working electrode, wherein the first and secondbarrier layers are independently formed (e.g., formed separately on thetwo electroactive surfaces). In some further embodiments, the physicaldiffusion barrier includes a first resistance domain formed on the firstworking electrode and a second resistance domain formed on the secondworking electrode, and wherein the first and second resistance domainsare configured and arranged to reduce diffusion of the measurablespecies (e.g., crosstalk) from the active enzymatic portion of thesensor to the second electroactive surface by at least 2-fold. In apreferred embodiment, the physical diffusion barrier can reduce thediffusion of the measurable species (e.g., crosstalk) by at least10-fold.

In some embodiments, the continuous glucose sensor includes first andsecond working electrodes, each working electrode including anelectroactive surface (each including an area) disposed beneath a sensormembrane. As described elsewhere herein, the first electroactive surfaceis disposed beneath an active enzymatic portion of the membrane and thesecond electroactive surface is disposed beneath a non-enzymatic portionof the membrane. Preferably, the sensor includes a physical diffusionbarrier, and the first and second electroactive surfaces are disposedsufficiently close together that the first and second noise components(detected by the first and second working electrodes) are substantiallyequivalent. In some embodiments, the distance between the first andsecond electroactive surfaces is less than about twice the thickness ofthe membrane. In some embodiments, the first and second electroactivesurfaces are spaced a distance that is less than or equal to about acrosstalk diffusion distance of a measurable species, such as the H₂O₂produced in the active enzymatic portion of the sensor membrane. In someembodiments, the physical diffusion barrier is configured and arrangedto physically block some diffusion of the measurable species from theactive enzymatic portion of the membrane to the second electroactivesurface (e.g., crosstalk). In preferred embodiments, the physicaldiffusion barrier blocks a substantial amount of the measurable species,such that there is substantially no signal associated with crosstalkmeasured at the second working electrode. In some embodiments, thephysical diffusion barrier is a discontinuous portion of the membranedisposed between the first and second electroactive surfaces. In someembodiments, the physical diffusion barrier is a first barrier layerformed on the first electrode and a second barrier layer formed on thesecond electrode, wherein the first and second barrier layers areindependently formed. In some embodiments, the physical diffusionbarrier includes a first resistance domain formed on the first electrodeand a second resistance domain formed on the second electrode.Preferably, the first and second resistance domains reduce diffusion ofthe measurable species (e.g., crosstalk) by at least 2-fold. In morepreferred embodiments, the diffusion of the measurable species isreduced by at least 10-fold. In some embodiments, the membrane is aninsulator that insulates the first working electrode from the secondworking electrodes. In some further embodiments, the first and secondareas are sufficiently large that the first and second noise componentsare substantially equivalent.

Sensor Electronics

The analyte sensor system has electronics, also referred to as a“computer system” that can include hardware, firmware, and/or softwarethat enable measurement and processing of data associated with analytelevels in the host. In one exemplary embodiment, the electronics includea potentiostat, a power source for providing power to the sensor, andother components useful for signal processing. In another exemplaryembodiment, the electronics include an RF module for transmitting datafrom sensor electronics to a receiver remote from the sensor. In anotherexemplary embodiment, the sensor electronics are wired to a receiver,which records the data and optionally transmits the data to a remotelocation, such as but not limited to a nurse's station, for tracking thehost's progress and to alarm the staff is a hypoglycemic episode occurs.In another exemplary embodiment, the sensor electronics include aprocessor module configured to and/or comprises programming forprocessing sensor data, as described elsewhere herein. In some exemplaryembodiments, the sensor electronics include a receiving module forreceiving sensor signals, such as but not limited to from the workingelectrode(s), and/or externally provided reference data points. In someembodiments, the processor module can include the receiving module. Theprocessor module and the receiving module can be located together and/orin any combination of sensor electronics local to and/or remote from thesensor.

Various components of the electronics of the sensor system can bedisposed on or proximal to the analyte sensor, such as but not limitedto disposed on the fluid coupler 20 of the system, such as theembodiment shown in FIG. 1A. In another embodiment, wherein the sensoris integrally formed on the catheter (e.g., see FIG. 2A) and theelectronics are disposed on or proximal to the connector 218. In someembodiments, only a portion of the electronics (e.g., the potentiostat)is disposed on the device (e.g., proximal to the sensor), while theremaining electronics are disposed remotely from the device, such as ona stand or by the bedside. In a further embodiment, a portion of theelectronics can be disposed in a central location, such as a nurse'sstation.

In additional embodiments, some or all of the electronics can be inwired or wireless communication with the sensor and/or other portions ofthe electronics. For example, a potentiostat disposed on the device canbe wired to the remaining electronics (e.g., a processor, a recorder, atransmitter, a receiver, etc.), which reside on the bedside. In anotherexample, some portion of the electronics is wirelessly connected toanother portion of the electronics, such as by infrared (IR) or RF. Inone embodiment, a potentiostat resides on the fluid coupler and isconnected to a receiver by RF; accordingly, a battery, RF transmitter,and/or other minimally necessary electronics are provided with the fluidcoupler and the receiver includes an RF receiver.

Preferably, the potentiostat is operably connected to the electrode(s)(such as described above), which biases the sensor to enable measurementof a current signal indicative of the analyte concentration in the host(also referred to as the analog portion). In some embodiments, thepotentiostat includes a resistor that translates the current intovoltage. In some alternative embodiments, a current to frequencyconverter is provided that is configured to continuously integrate themeasured current, for example, using a charge counting device.

In some embodiments, the electronics include an A/D converter thatdigitizes the analog signal into a digital signal, also referred to as“counts” for processing. Accordingly, the resulting raw data stream incounts, also referred to as raw sensor data, is directly related to thecurrent measured by the potentiostat.

Typically, the electronics include a processor module that includes thecentral control unit that controls the processing of the sensor system.In some embodiments, the processor module includes a microprocessor,however a computer system other than a microprocessor can be used toprocess data as described herein, for example an ASIC can be used forsome or all of the sensor's central processing. The processor typicallyprovides semi-permanent storage of data, for example, storing data suchas sensor identifier (ID) and programming to process data streams (forexample, programming for data smoothing and/or replacement of signalartifacts such as is described in U.S. Patent Publication No.US-2005-0043598-A1). The processor additionally can be used for thesystem's cache memory, for example for temporarily storing recent sensordata. In some embodiments, the processor module comprises memory storagecomponents such as ROM, RAM, dynamic-RAM, static-RAM, non-static RAM,EEPROM, rewritable ROMs, flash memory, and the like.

In some embodiments, the processor module comprises a digital filter(e.g., programming), for example, an infinite impulse response (IIR) orfinite impulse response (FIR) filter, configured to smooth the raw datastream from the A/D converter. Generally, digital filters are programmedto filter data sampled at a predetermined time interval (also referredto as a sample rate). In some embodiments, wherein the potentiostat isconfigured to measure the analyte at discrete time intervals, these timeintervals determine the sample rate of the digital filter. In somealternative embodiments, wherein the potentiostat is configured tocontinuously measure the analyte, for example, using acurrent-to-frequency converter as described above, the processor modulecan be programmed to request a digital value from the A/D converter at apredetermined time interval, also referred to as the acquisition time.In these alternative embodiments, the values obtained by the processorare advantageously averaged over the acquisition time due the continuityof the current measurement. Accordingly, the acquisition time determinesthe sample rate of the digital filter. In preferred embodiments, theprocessor module is configured with a programmable acquisition time,namely, the predetermined time interval for requesting the digital valuefrom the A/D converter is programmable by a user within the digitalcircuitry of the processor module. An acquisition time of from about 2seconds to about 512 seconds is preferred; however any acquisition timecan be programmed into the processor module. A programmable acquisitiontime is advantageous in optimizing noise filtration, time lag, andprocessing/battery power.

In some embodiments, the processor module is configured to and/orcomprises programming to build the data packet for transmission to anoutside source, for example, an RF transmission to a receiver.Generally, the data packet comprises a plurality of bits that caninclude a preamble, a unique identifier identifying the electronicsunit, the receiver, or both, (e.g., sensor ID code), data (e.g., rawdata, filtered data, and/or an integrated value) and/or error detectionor correction. Preferably, the data (transmission) packet has a lengthof from about 8 bits to about 128 bits, preferably about 48 bits;however, larger or smaller packets can be desirable in certainembodiments. The processor module can be configured to transmit anycombination of raw and/or filtered data. In one exemplary embodiment,the transmission packet contains a fixed preamble, a unique ID of theelectronics unit, a single five-minute average (e.g., integrated) sensordata value, and a cyclic redundancy code (CRC).

In some embodiments, the processor module further comprises atransmitter portion that determines the transmission interval of thesensor data to a receiver, and the like. In some embodiments, thetransmitter portion, which determines the interval of transmission, isconfigured to be programmable. In one such embodiment, a coefficient canbe chosen (e.g. a number of from about 1 to about 100, or more), whereinthe coefficient is multiplied by the acquisition time (or samplingrate), such as described above, to define the transmission interval ofthe data packet. Thus, in some embodiments, the transmission interval isprogrammable from about 2 seconds to about 850 minutes, more preferablyfrom about 30 second to about 5 minutes; however, any transmissioninterval can be programmable or programmed into the processor module.However, a variety of alternative systems and methods for providing aprogrammable transmission interval can also be employed. By providing aprogrammable transmission interval, data transmission can be customizedto meet a variety of design criteria (e.g. reduced battery consumption,timeliness of reporting sensor values, etc.)

In some embodiments, the processor is further configured to and/orfurther comprises programming to perform the processing, such as storingdata, analyzing data streams, calibrating analyte sensor data,estimating analyte values, comparing estimated analyte values with timecorresponding measured analyte values, analyzing a variation ofestimated analyte values, downloading data, and controlling the userinterface by providing analyte values, prompts, messages, warnings,alarms, and the like. In such cases, the processor includes hardware andsoftware that performs the processing described herein, for exampleflash memory provides permanent or semi-permanent storage of data,storing data such as sensor ID, receiver ID, and programming to processdata streams (for example, programming for performing estimation andother algorithms described elsewhere herein) and random access memory(RAM) stores the system's cache memory and is helpful in dataprocessing. Alternatively, some portion of the data processing (such asdescribed with reference to the processor elsewhere herein) can beaccomplished at another (e.g., remote) processor and can be configuredto be in wired or wireless connection therewith.

In some embodiments, an output module, which is integral with and/oroperatively connected with the processor, includes programming forgenerating output based on the data stream received from the sensorsystem and it's processing incurred in the processor. In someembodiments, output is generated via a user interface.

In some embodiments, a user interface is provided integral with (e.g.,on the patient inserted medical device), proximal to (e.g., a receivernear the medical device including bedside or on a stand), or remote fromthe sensor electronics (e.g., at a central station such as a nurse'sstation), wherein the user interface comprises a keyboard, speaker,vibrator, backlight, liquid crystal display (LCD) screen, and one ormore buttons. The components that comprise the user interface includecontrols to allow interaction of the user with the sensor system. Thekeyboard can allow, for example, input of user information, such asmealtime, exercise, insulin administration, customized therapyrecommendations, and reference analyte values. The speaker can produce,for example, audible signals or alerts for conditions such as presentand/or estimated hyperglycemic or hypoglycemic conditions. The vibratorcan provide, for example, tactile signals or alerts for reasons such asdescribed with reference to the speaker, above. The backlight can beprovided, for example, to aid a user in reading the LCD in low lightconditions. The LCD can be provided, for example, to provide the userwith visual data output, such as is described in U.S. Patent PublicationNo. US-2005-0203360-A1. In some embodiments, the LCD is atouch-activated screen, enabling each selection by a user, for example,from a menu on the screen. The buttons can provide for toggle, menuselection, option selection, mode selection, and reset, for example. Insome alternative embodiments, a microphone can be provided to allow forvoice-activated control.

In some embodiments, prompts or messages can be displayed on the userinterface to convey information to the user, such as reference outliervalues, requests for reference analyte values, therapy recommendations,deviation of the measured analyte values from the estimated analytevalues, and the like. Additionally, prompts can be displayed to guidethe user through calibration or trouble-shooting of the calibration.

Additionally, data output from the output module can provide wired orwireless, one- or two-way communication between the user interface andan external device. The external device can be any device that whereininterfaces or communicates with the user interface. In some embodiments,the external device is a computer, and the system is able to downloadhistorical data for retrospective analysis by the patient or physician,for example. In some embodiments, the external device is a modem orother telecommunications station, and the system is able to send alerts,warnings, emergency messages, and the like, via telecommunication linesto another party, such as a doctor or family member. In someembodiments, the external device is an insulin pen, and the system isable to communicate therapy recommendations, such as insulin amount andtime to the insulin pen. In some embodiments, the external device is aninsulin pump, and the system is able to communicate therapyrecommendations, such as insulin amount and time to the insulin pump.The external device can include other technology or medical devices, forexample pacemakers, implanted analyte sensor patches, other infusiondevices, telemetry devices, and the like.

The user interface, including keyboard, buttons, a microphone (notshown), and optionally the external device, can be configured to allowinput of data. Data input can be helpful in obtaining information aboutthe patient (for example, meal time, insulin administration, and thelike), receiving instructions from a physician (for example, customizedtherapy recommendations, targets, and the like), and downloadingsoftware updates, for example. Keyboard, buttons, touch-screen, andmicrophone are all examples of mechanisms by which a user can input datadirectly into the receiver. A server, personal computer, personaldigital assistant, insulin pump, and insulin pen are examples ofexternal devices that can provide useful information to the receiver.Other devices internal or external to the sensor that measure otheraspects of a patient's body (for example, temperature sensor,accelerometer, heart rate monitor, oxygen monitor, and the like) can beused to provide input helpful in data processing. In one embodiment, theuser interface can prompt the patient to select an activity most closelyrelated to their present activity, such as medication taken, surgicalprocedures, and the like, which can be helpful in linking to anindividual's physiological patterns, or other data processing. Inanother embodiment, a temperature sensor and/or heart rate monitor canprovide information helpful in linking activity, metabolism, and glucoseexcursions of an individual. While a few examples of data input havebeen provided here, a variety of information can be input, which can behelpful in data processing.

Algorithms

In some embodiments, calibration of an analyte sensor can be required,which includes data processing that converts sensor data signal into anestimated analyte measurement that is meaningful to a user. In general,the sensor system has a computer system (e.g., within the electronics)that receives sensor data (e.g., a data stream), including one or moretime-spaced sensor data points, measured by the sensor. The sensor datapoint(s) can be smoothed (filtered) in certain embodiments using afilter, for example, a finite impulse response (FIR) or infinite impulseresponse (IIR) filter. During the initialization of the sensor, prior toinitial calibration, the system can receive and store uncalibratedsensor data, however it can be configured to not display any data to theuser until initial calibration and, optionally, stabilization of thesensor has been established. In some embodiments, the data stream can beevaluated to determine sensor break-in (equilibration of the sensor invitro or in vivo).

In some embodiments, the system is configured to receive reference datafrom a reference analyte monitor, including one or more reference datapoints, also referred to as calibration information in some embodiments.The monitor can be of any suitable configuration. For example, in oneembodiment, the reference analyte points can comprise results from aself-monitored blood analyte test (e.g., from a finger stick test, YSI,Beckman Glucose Analyzer, and the like), such as those described in U.S.Pat. No. 6,045,567, U.S. Pat. No. 6,156,051, U.S. Pat. No. 6,197,040,U.S. Pat. No. 6,284,125, U.S. Pat. No. 6,413,410, and U.S. Pat. No.6,733,655. In one such embodiment, the user can administer aself-monitored blood analyte test to obtain an analyte value (e.g.,point) using any suitable analyte sensor, and then enter the numericanalyte value into the computer system. In another such embodiment, aself-monitored blood analyte test comprises a wired or wirelessconnection to the computer system so that the user simply initiates aconnection between the two devices, and the reference analyte data ispassed or downloaded between the self-monitored blood analyte test andthe system. In yet another such embodiment, the self-monitored analytetest is integral with the receiver so that the user simply provides ablood sample to the receiver, and the receiver runs the analyte test todetermine a reference analyte value.

In some alternative embodiments, the reference data is based on sensordata from another substantially continuous analyte sensor such asdescribed herein, or another type of suitable continuous analyte sensor.In an embodiment employing a series of two or more continuous sensors,the sensors can be employed so that they provide sensor data in discreteor overlapping periods. In such embodiments, the sensor data from onecontinuous sensor can be used to calibrate another continuous sensor, orbe used to confirm the validity of a subsequently employed continuoussensor.

In some embodiments, the sensor system is coupled to a blood analysisdevice that periodically or intermittently collects a sample of thehost's blood (e.g., through the sensor system) and measures the host'sglucose concentration. In some embodiments, the blood analysis devicecollects a blood sample from the host about every 30 minutes, everyhour, or every few hours (e.g., 2, 3, 4, 5, 6, 8, 9 or 10 hours orlonger). In other embodiments, the blood analysis device can beactivated manually (e.g., by a healthcare worker) to collect and analyzea blood sample from the host. The glucose concentration data generatedby the blood analysis device can be used by the sensor system forcalibration data. In some embodiments, the sensor system canelectronically receive (either wired or wirelessly) these calibrationdata (from the blood analysis device). In other embodiments, thesecalibration data can be entered into the sensor system (e.g., sensorsystem electronics) by hand (e.g., manually entered by a healthcareworker).

In some embodiments, the sensor system is provided with one or morecalibration solutions (e.g., glucose solutions). In some embodiments,the sensor is shipped in a calibration solution (e.g., soaked). Thesensor is activated to calibrate itself (using the calibration solutionin which it was shipped) before insertion into the host. In someembodiments, the sensor is shipped (e.g., soaked or dry) with one ormore vials of calibration solution. The sensor can be soaked (e.g.,sequentially) in the vial(s) of calibration solution; calibration datapoints collected and the sensor calibrated using those calibrationpoints, before inserting the sensor into the host.

In one exemplary embodiment, the sensor is a glucose sensor, and it isshipped soaking in a sterile 50 mg/dl glucose solution with twoaccompanying calibration solutions (e.g., 100 mg/dl and 200 mg/dlsterile glucose solutions). Prior to insertion into the host,calibration data points are collected with the sensor in the 50 mg/dl,100 mg/dl and 200 mg/dl glucose solutions respectively. The sensorsystem can be calibrated using the collected calibration data points(e.g., using regression as described in more detail elsewhere herein).In an alternative exemplary embodiment, the sensor is shipped dry (e.g.,not soaking in a solution or buffer) with at least one calibrationsolution, for calibrating the sensor prior to insertion into the host.In some embodiments, a hand held glucose monitor (e.g., SMBG devicedescribed herein) can test the calibration solutions to generatecalibration data points, which are transferred electronically ormanually to the sensor system for calibration.

In some embodiments, a data matching module, also referred to as theprocessor module, is configured to and/or comprises programming tomatches reference data (e.g. one or more reference analyte data points)with substantially time corresponding sensor data (e.g., one or moresensor data points) to provide one or more matched data pairs. Onereference data point can be matched to one time corresponding sensordata point to form a matched data pair. Alternatively, a plurality ofreference data points can be averaged (e.g., equally or non-equallyweighted average, mean-value, median, and the like) and matched to onetime corresponding sensor data point to form a matched data pair, onereference data point can be matched to a plurality of time correspondingsensor data points averaged to form a matched data pair, or a pluralityof reference data points can be averaged and matched to a plurality oftime corresponding sensor data points averaged to form a matched datapair.

In some embodiments, a calibration set module, also referred to as thecalibration module or processor module, is configured to and/orcomprises programming to form an initial calibration set from a set ofone or more matched data pairs, which are used to determine therelationship between the reference analyte data and the sensor analytedata. The matched data pairs, which make up the initial calibration set,can be selected according to predetermined criteria. The criteria forthe initial calibration set can be the same as, or different from, thecriteria for the updated calibration sets. In certain embodiments, thenumber (n) of data pair(s) selected for the initial calibration set isone. In other embodiments, n data pairs are selected for the initialcalibration set wherein n is a function of the frequency of the receivedreference data points. In various embodiments, two data pairs make upthe initial calibration set or six data pairs make up the initialcalibration set. In an embodiment wherein a substantially continuousanalyte sensor provides reference data, numerous data points are used toprovide reference data from more than 6 data pairs (e.g., dozens or evenhundreds of data pairs). In one exemplary embodiment, a substantiallycontinuous analyte sensor provides 288 reference data points per day(every five minutes for twenty-four hours), thereby providing anopportunity for a matched data pair 288 times per day, for example.While specific numbers of matched data pairs are referred to in thepreferred embodiments, any suitable number of matched data pairs per agiven time period can be employed.

In some embodiments, a conversion function module, also referred to asthe conversion module or processor module, is configured to and/orcomprises programming to use the calibration set to create a conversionfunction. The conversion function substantially defines the relationshipbetween the reference analyte data and the analyte sensor data.

A variety of known methods can be used with the preferred embodiments tocreate the conversion function from the calibration set. In oneembodiment, wherein a plurality of matched data points form thecalibration set, a linear least squares regression is used to calculatethe conversion function; for example, this regression calculates a slopeand an offset using the equation y=mx+b. A variety of regression orother conversion schemes can be implemented herein.

In some alternative embodiments, the sensor is a dual-electrode system.In one such dual-electrode system, a first electrode functions as ahydrogen peroxide sensor including a membrane system containingglucose-oxidase disposed thereon, which operates as described herein. Asecond electrode is a hydrogen peroxide sensor that is configuredsimilar to the first electrode, but with a modified membrane system(with the enzyme domain removed, for example). This second electrodeprovides a signal composed mostly of the baseline signal, b.

In some dual-electrode systems, the baseline signal is (electronicallyor digitally) subtracted from the glucose signal to obtain a glucosesignal substantially without baseline. Accordingly, calibration of theresultant difference signal can be performed by solving the equationy=mx with a single paired measurement. Calibration of the implantedsensor in this alternative embodiment can be made less dependent on thevalues/range of the paired measurements, less sensitive to error inmanual blood glucose measurements, and can facilitate the sensor's useas a primary source of glucose information for the user. U.S. PatentPublication No. US-2005-0143635-A1 describes systems and methods forsubtracting the baseline from a sensor signal.

In some alternative dual-electrode system embodiments, the analytesensor is configured to transmit signals obtained from each electrodeseparately (e.g., without subtraction of the baseline signal). In thisway, the receiver can process these signals to determine additionalinformation about the sensor and/or analyte concentration. For example,by comparing the signals from the first and second electrodes, changesin baseline and/or sensitivity can be detected and/or measured and usedto update calibration (e.g., without the use of a reference analytevalue). In one such example, by monitoring the corresponding first andsecond signals over time, an amount of signal contributed by baselinecan be measured. In another such example, by comparing fluctuations inthe correlating signals over time, changes in sensitivity can bedetected and/or measured.

In some alternative embodiments, the processor module is configured toand/or comprises programming to use a regression equation y=mx+b tocalculate the conversion function; however, prior information can beprovided for m and/or b, thereby enabling calibration to occur withfewer paired measurements. In one calibration technique, priorinformation (e.g. obtained from in vivo or in vitro tests) determines asensitivity of the sensor and/or the baseline signal of the sensor byanalyzing sensor data from measurements taken by the sensor (e.g. priorto inserting the sensor). For example, if there exists a predictiverelationship between in vitro sensor parameters and in vivo parameters,then this information can be used by the calibration procedure. Forexample, if a predictive relationship exists between in vitrosensitivity and in vivo sensitivity, m≈f(m_(in vitro)) then thepredicted m can be used, along with a single matched pair, to solve forb (b=y−mx). If, in addition, b can be assumed=0, for example with adual-electrode configuration that enables subtraction of the baselinefrom the signal such as described above, then both m and b are known apriori, matched pairs are not needed for calibration, and the sensor canbe completely calibrated e.g. without the need for reference analytevalues (e.g. values obtained after implantation in vivo.)

In another alternative embodiment, prior information can be provided toguide or validate the baseline (b) and/or sensitivity (m) determinedfrom the regression analysis. In this embodiment, boundaries can be setfor the regression line that defines the conversion function such thatworking sensors are calibrated accurately and easily (with two points),and non-working sensors are prevented from being calibrated. If theboundaries are drawn too tightly, a working sensor may not enter intocalibration. Likewise, if the boundaries are drawn too loosely, thescheme can result in inaccurate calibration or can permit non-workingsensors to enter into calibration. For example, subsequent to performingregression, the resulting slope and/or baseline are tested to determinewhether they fall within a predetermined acceptable threshold(boundaries). These predetermined acceptable boundaries can be obtainedfrom in vivo or in vitro tests (e.g. by a retrospective analysis ofsensor sensitivities and/or baselines collected from a set ofsensors/patients, assuming that the set is representative of futuredata).

In some alternative embodiments, the sensor system does not requireinitial and/or update calibration by the host; in these alternativeembodiments, also referred to as “zero-point calibration” embodiments,use of the sensor system without requiring a reference analytemeasurement for initial and/or update calibration is enabled. Ingeneral, the systems and methods of the preferred embodiments providefor stable and repeatable sensor manufacture, particularly when tightlycontrolled manufacturing processes are utilized. Namely, a batch ofsensors of the preferred embodiments can be designed with substantiallythe same baseline (b) and/or sensitivity (m) (+/−10%) when tested invitro. Additionally, the sensor of the preferred embodiments can bedesigned for repeatable m and b in vivo. Thus, an initial calibrationfactor (conversion function) can be programmed into the sensor (sensorelectronics and/or receiver electronics) that enables conversion of rawsensor data into calibrated sensor data solely using informationobtained prior to implantation (namely, initial calibration does notrequire a reference analyte value). Additionally, to obviate the needfor recalibration (update calibration) during the life of the sensor,the sensor is designed to minimize drift of the sensitivity and/orbaseline over time in vivo. Accordingly, the preferred embodiments canbe manufactured for zero point calibration.

In some embodiments, a sensor data transformation module, also referredto as the calibration module, conversion module, or processor module, isconfigured to and/or comprises programming to use the conversionfunction to transform sensor data into substantially real-time analytevalue estimates, also referred to as calibrated data, or convertedsensor data, as sensor data is continuously (or intermittently) receivedfrom the sensor. For example, the sensor data, which can be provided tothe receiver in “counts,” is translated in to estimate analyte value(s)in mg/dL. In other words, the offset value at any given point in timecan be subtracted from the raw value (e.g., in counts) and divided bythe slope to obtain the estimate analyte value:

${{mg}\text{/}{dL}} = \frac{( {{rawvalue} - {offset}} )}{slope}$

In some embodiments, an output module is configured to and/or comprisesprogramming to provide output to the user via the user interface. Theoutput is representative of the estimated analyte value, which isdetermined by converting the sensor data into a meaningful analytevalue. User output can be in the form of a numeric estimated analytevalue, an indication of directional trend of analyte concentration,and/or a graphical representation of the estimated analyte data over aperiod of time, for example. Other representations of the estimatedanalyte values are also possible, for example audio and tactile.

In some embodiments, annotations are provided on the graph; for example,bitmap images are displayed thereon, which represent events experiencedby the host. For example, information about meals, medications, insulin,exercise, sensor insertion, sleep, and the like, can be obtained by thereceiver (by user input or receipt of a transmission from anotherdevice) and displayed on the graphical representation of the host'sglucose over time. It is believed that illustrating a host's life eventsmatched with a host's glucose concentration over time can be helpful ineducating the host to his or her metabolic response to the variousevents.

In yet another alternative embodiment, the sensor utilizes one or moreadditional electrodes to measure an additional analyte. Suchmeasurements can provide a baseline or sensitivity value for use incalibrating the sensor. Furthermore, baseline and/or sensitivity valuescan be used to trigger events such as digital filtering of data orsuspending display of data, all of which are described in more detail inU.S. Patent Publication No. US-2005-0143635-A1.

In one exemplary embodiment, the sensor can be calibrated by acalibration solution. For example, after the sensor system has beeninserted into the host, a calibration solution can be injected so as topass across the electroactive surface of the analyte-measuring electrodeand the sensor calibrated thereby. For example, the saline drip can bechanged to a known IV glucose or dextrose solution (e.g., D50—a 50%dextrose solution, or D5W—a 5% dextrose solution). In one embodiment, aknown volume of D5W is infused into the host at a known rate over apredetermined period of time (e.g., 5, 10, 15 or 20 minutes, or forshorter or longer periods). During and/or after the period of infusion,the sensor measures the signal at the analyte-measuring workingelectrode. The system, knowing the specifications of the infusedcalibration solution (also referred to as a calibration information insome embodiments), can calibrate the signal to obtain host's glucoseconcentration as is appreciated by one skilled in the art. In a furtherembodiment, two or more glucose or dextrose solutions can be infused,with a corresponding signal being measured during each infusion, toprovide additional data for sensor calibration. Calibration can beperformed after the sensor has first been inserted into the host, aftera break-in time, at two or more different levels (high/low), regularly,intermittently, in response to sensor drift/shift, automatically or anyother time when calibration is required. In some alternativeembodiments, calibration can be determined during sensor break-in, suchas described in more detail elsewhere herein.

In some circumstances, catheters are flushed with saline. For example,the analyte sensor system of the preferred embodiments can be flushedwith saline prior to application of control solutions, after which apredetermined amount of glucose solution is flushed by the sensor, asdescribed above, and the sensor is calibrated there from.

In still another embodiment, a blood sample can be withdrawn from anartery or vein, and used to calibrate the sensor, for example, by usinga hand-held glucose meter, by an automatic extracorporeal glucose sensorsuch as but not limited to in conjunction with an automated bedsideclinical chemistry device, or by sending the blood sample to theclinical laboratory for glucose analysis, after which the data is input(e.g., into the electronics associated with the sensor system).

In some embodiments, the sensor can be calibrated (and/or re-calibrated)during use (after initial calibration), for example, by withdrawing oneor more blood samples (also referred to as calibration information insome embodiments), through the catheter (see FIGS. 1 and 2) and used forcalibration of the sensor, such as by measuring the glucoseconcentration of the blood sample with an additional system, such as butnot limited to a hand-held glucose meter, optical methods or additionalelectrochemical methods. Blood samples can be withdrawn manually orautomatically; additionally or alternatively, blood samples arewithdrawn at regular intervals or at selected times, for example, usingan extracorporeal blood analysis device as described herein.

In another embodiment of sensor calibration (and/or re-calibration)during use, a calibration solution (e.g., 40 mg/dL equivalent glucose,D540 or D5W) can be flushed through or by the sensor to enablecalibration of the sensor (e.g., at one time, intermittently, orcontinuously), such as described in more detail above. In theseembodiments, calibration solution can be flushed manually orautomatically through the system; additionally or alternatively,calibration solution can be flushed at regular intervals or at selectedtimes. In one exemplary embodiment, the system can be provided with adual lumen, one for saline and another for the control solution.Additionally, the system is configured to automatically switch from thesaline to control solution and perform the real-time system calibration,and then switch back to the saline solution.

Calibration Systems and Methods for Dual-Electrode Sensors

As described herein, continuous analyte sensors define a relationshipbetween a sensor-generated signal and a reference measurement that ismeaningful to a user (for example, blood glucose in mg/dL). This definedrelationship must be monitored to ensure that the continuous analytesensor maintains a substantially accurate calibration and therebycontinually provides meaningful values to a user. Unfortunately, bothsensitivity m and baseline b changes can occur during in vivo sensoruse, which requires calibration updates (e.g., recalibration).Generally, any physical properties of the sensor or the fluidsurrounding the sensor can influence diffusion or transport of moleculesthrough the membrane, and thereby produce fluctuations in sensitivityand/or baseline, which in turn affect the sensor's calibration. Thesephysical properties include, but are not limited to, blockage of sensorsurface area due to cells and/or blood clotting at the membrane,biofouling, blood flow/sheer rate, blood pH, temperature, hematocrit,interfering drugs in the host's system, certain metabolic processes,disrupted host electrolyte balance due to disease and/or trauma,thickness and/or components of the sensor's membrane system, and thelike.

In one aspect of the preferred embodiments, systems and methods areprovided for measuring changes in sensitivity m, also referred to aschanges in solute transport or membrane changes, of an analyte sensorimplanted in a host over a time period. Preferably, the sensitivityvalue is a signal obtained by measuring a constant analyte other thanthe analyte being measured by the analyte sensor. For example, in aglucose sensor, a non-glucose constant analyte is measured, wherein thesignal is measured beneath the membrane system on the glucose sensor.While not wishing to be bound by theory, it is believed that bymonitoring the sensitivity m over a time period, a change associatedwith solute transport through the membrane system (e.g., diffusion therethrough) can be measured and used as an indication of a sensitivitychange in the analyte measurement. In other words, a membrane monitor isprovided, which is capable of monitoring changes in the membranesurrounding an implantable device, thereby enabling the measurement ofsensitivity changes of an analyte sensor over time.

In some embodiments, the analyte sensor is provided with an auxiliaryelectrode (e.g., a second working electrode) configured as atransport-measuring electrode disposed beneath the membrane system. Thetransport-measuring electrode can be configured to measure any of anumber of substantially constant analytes or factors, such that a changemeasured by the transport-measuring electrode can be used to indicate achange in solute (for example, glucose) transport through the membranesystem. Some examples of substantially constant analytes or factors thatcan be measured include, but are not limited to, oxygen, carboxylicacids (such as urea), amino acids, hydrogen, pH, chloride, baseline, orthe like. Thus, the transport-measuring electrode provides anindependent measure of changes in solute transport to the membrane, andthus sensitivity changes over time.

In some embodiments, the transport-measuring electrode measures analytessimilar to the analyte being measured by the analyte sensor. Forexample, in some embodiments of a glucose sensor, water soluble analytesare believed to better represent the changes in sensitivity to glucoseover time than non-water soluble analytes (due to the water-solubilityof glucose), however relevant information may be ascertained from avariety of molecules. Although some specific examples are describedherein, one skilled in the art appreciates a variety of implementationsof sensitivity values that can be used as to qualify or quantify solutetransport through the membrane of the analyte sensor.

In one embodiment of a glucose sensor, the transport-measuring electrodeis configured to measure urea, which is a water-soluble constant analytethat is known to react directly or indirectly at a hydrogen peroxidesensing electrode (similar to the working electrode of the glucosesensor example described in more detail above). In one exemplaryimplementation wherein urea is directly measured by thetransport-measuring electrode, the glucose sensor comprises a membranesystem as described in more detail above, however, does not include anactive interference domain or active enzyme directly above thetransport-measuring electrode, thereby allowing the urea to pass throughthe membrane system to the electroactive surface for measurementthereon. In one alternative exemplary implementation wherein urea isindirectly measured by the transport-measuring electrode, the glucosesensor comprises a membrane system as described in more detail above,and further includes an active uricase oxidase domain located directlyabove the transport-measuring electrode, thereby allowing the urea toreact at the enzyme and produce hydrogen peroxide, which can be measuredat the electroactive surface thereon.

In some embodiments, the change in sensitivity m is measured bymeasuring a change in oxygen concentration and to indicate whenrecalibration of the system may be advantageous. In one alternativeembodiment, oxygen is measured using pulsed amperometric detection onthe glucose-measuring working electrode (eliminating the need for aseparate auxiliary electrode), such as by switching the appliedpotential from +0.6 mV to −0.6 mV. In another embodiment, the auxiliaryelectrode is configured as an oxygen-measuring electrode. In someembodiments, a third electrode can be configured as an oxygen-measuringelectrode. In another embodiment, an oxygen sensor (not shown) is addedto the glucose sensor, as is appreciated by one skilled in the art,eliminating the need for an auxiliary electrode.

In some embodiments, sensitivity changes in an intravasculardual-electrode continuous analyte sensor can be provided via a referencesensor, such as an oxygen sensor, as described in the section entitled“Optical Detection.” In some embodiments, auto-calibration (e.g.,without a manual, external (to the system) reference value) is enabledby exposing the dual-electrode sensor and the reference sensorsimultaneously to a reference/calibration solution, whereby referencedata is provided for calibration of the sensor data. Advantageously, adual-electrode continuous analyte sensor is configured to measurebaseline b, and changes in sensitivity m are measured by exposure of thedual-electrode sensor to the reference/calibration solution. In someembodiments, the system is configured for “on demand” auto-calibration,such as via configuring the system such that a user can initiate (e.g.,command) auto-calibration via a user interface (e.g., via selection froma menu, pressing a pre-programmed button and the like).

In some alternative embodiments, sensitivity changes can be used toupdate calibration. For example, the measured change in transport can beused to update the sensitivity m in the calibration equation. While notwishing to be bound by theory, it is believed that in some embodiments,the sensitivity m of the calibration of the glucose sensor issubstantially proportional to the change in solute transport measured bythe transport-measuring electrode.

It should be appreciated by one skilled in the art that in someembodiments, the implementation of sensitivity values of the preferredembodiments typically necessitate an addition to, or modification of,the existing electronics (for example, potentiostat configuration orsettings) of the glucose sensor and/or receiver.

In some embodiments, the signal from the oxygen measuring electrode maybe digitally low-pass filtered (for example, with a passband of 0-10⁻⁵Hz, dc-24 hour cycle lengths) to remove transient fluctuations inoxygen, due to local ischemia, postural effects, periods of apnea, orthe like. Since oxygen delivery to tissues is held in tight homeostaticcontrol, this filtered oxygen signal should oscillate about a relativelyconstant. In the interstitial fluid, it is thought that the levels areabout equivalent with venous blood (40 mmHg). Once implanted, changes inthe mean of the oxygen signal (for example, >5%) may be indicative ofchange in transport through the membrane (change in sensor sensitivityand/or baseline due to changes in solute transport) and the need forsystem recalibration.

The oxygen signal may also be used in its unfiltered or a minimallyfiltered form to detect or predict oxygen deprivation-induced artifactin the glucose signal, and to control display of data to the user, orthe method for smoothing, digital filtering, or otherwise replacement ofglucose signal artifact. In some embodiments, the oxygen sensor may beimplemented in conjunction with any signal artifact detection orprediction that may be performed on the counter electrode or workingelectrode voltage signals of the electrode system. U.S. PatentPublication No. US-2005-0043598-A1, which is incorporated by referencein its entirety herein, describes some methods of signal artifactdetection and replacement that may be useful such as described herein.

Preferably, the transport-measuring electrode is located within the samelocal environment as the electrode system associated with themeasurement of glucose, such that the transport properties at thetransport-measuring electrode are substantially similar to the transportproperties at the glucose-measuring electrode.

In a second aspect the preferred embodiments, systems and methods areprovided for measuring baseline, namely non-glucose relatedelectroactive compounds in the host. Preferably the auxiliary workingelectrode (e.g., second working electrode, non-enzymatic workingelectrode) is configured to measure the baseline of the analyte sensorover time. In some embodiments, the glucose-measuring working electrode(e.g., first working electrode) is a hydrogen peroxide sensor coupled toa membrane system containing an active enzyme located above theelectrode. In some embodiments, the auxiliary working electrode (e.g.,second working electrode) is another hydrogen peroxide sensor that isconfigured similar to the glucose-measuring working electrode however aportion of the membrane system above the base-measuring electrode doesnot have active enzyme therein, such as described in more detail withreference to FIG. 3D. The auxiliary working electrode provides a signalsubstantially comprising the baseline signal, b, which can be (forexample, electronically or digitally) subtracted from the glucose signalobtained from the glucose-measuring working electrode to obtain thesignal contribution due to glucose only according to the followingequation:

Signal_(glucose only)=Signal_(glucose-measuring working electrode)−Signal_(baseline-measuring working electrode)

In some embodiments, electronic subtraction of the baseline signal fromthe glucose signal can be performed in the hardware of the sensor, forexample using a differential amplifier. In some alternative embodiments,digital subtraction of the baseline signal from the glucose signal canbe performed in the software or hardware of the sensor or an associatedreceiver, for example in the microprocessor.

One aspect the preferred embodiments provides for a simplifiedcalibration technique, wherein the variability of the baseline has beeneliminated (namely, subtracted). Namely, calibration of the resultantdifferential signal (Signal_(glucose only)) can be performed with asingle matched data pair by solving the following equation:

y=mx

While not wishing to be bound by theory, it is believed that bycalibrating using this simplified technique, the sensor is made lessdependent on the range of values of the matched data pairs, which can besensitive to human error in manual blood glucose measurements, forexample. Additionally, by subtracting the baseline at the sensor (ratherthan solving for the baseline b as in conventional calibration schemes),accuracy of the sensor may increase by altering control of this variable(baseline b) from the user to the sensor. It is additionally believedthat variability introduced by sensor calibration may be reduced.

In some embodiments, the glucose-measuring working electrode (e.g.,first working electrode) is a hydrogen peroxide sensor coupled to amembrane system containing an active enzyme located above the electrode,such as described in more detail above; however the baseline signal isnot subtracted from the glucose signal for calibration of the sensor.Rather, multiple matched data pairs are obtained in order to calibratethe sensor (for example using y=mx+b) in a conventional manner, and theauxiliary/second working electrode is used as an indicator of baselineshifts in the sensor signal. Namely, the auxiliary/second workingelectrode is monitored for changes above a certain threshold. When asignificant change is detected, the system can trigger a request (forexample, from the patient or caregiver) for a new reference glucosevalue (for example, SMBG), which can be used to recalibrate the sensor.By using the auxiliary/second working electrode signal as an indicatorof baseline shifts, recalibration requiring user interaction (namely,new reference glucose values) can be minimized due to timeliness andappropriateness of the requests. In some embodiments, the sensor isre-calibrated responsive to a baseline shifts exceeding a preselectedthreshold value. In some embodiments, the sensor is calibratedrepeatedly at a frequency responsive to the rate-of-change of thebaseline.

In yet another alternative embodiment, the electrode system of thepreferred embodiments is employed as described above, includingdetermining the differential signal of glucose less baseline current inorder to calibrate using the simplified equation (y=mx), and theauxiliary/second working electrode is further utilized as an indicatorof baseline shifts in the sensor signal. While not wishing to be boundby theory, it is believed that shifts in baseline may also correlateand/or be related to changes in the sensitivity m of the glucose signal.Consequently, a shift in baseline may be indicative of a change insensitivity m. Therefore, the auxiliary working electrode is monitoredfor changes above a certain threshold. When a significant change isdetected, the system can trigger a request (for example, from thepatient or caregiver) for a new reference glucose value (for example,SMBG), which can be used to recalibrate the sensor. By using theauxiliary (second) signal as an indicator of possible sensitivitychanges, recalibration requiring user interaction (new reference glucosevalues) can be minimized due to timeliness and appropriateness of therequests.

In yet another alternative embodiment, wherein a dual-electrode analytesystem is use, the baseline signal is (electronically or digitally)subtracted from the glucose+baseline signal to obtain a glucose signalsubstantially without baseline. Accordingly, calibration of theresultant difference signal can be performed by solving the equationy=mx using a sensitivity value (m), which can be obtained from 1) themeasured reference (calibrant) solution, b) by pairing a referenceanalyte signal with a reference analyte value (internal reference sensorexample) and/or 3) with a sensitivity value obtained a priori (e.g.,during sensor manufacture, such as but not limited to by testing in anisotonic solution). Accordingly, calibration of the implanted sensor inthis embodiment can be less sensitive or insensitive to user errorassociated with providing external reference measurements, and canfacilitate the sensor's use as a primary source of glucose informationfor the user. However, a single external reference value (e.g., from anexternal test device such as SMBG and/or YSI testing of a host bloodsample) can be used to calibrate the sensor in some embodiments. U.S.Patent Publication No. US-2005-0143635-A1 describes systems and methodsfor subtracting the baseline from a sensor signal.

It is noted that, in some embodiments, infrequent new matching datapairs (e.g., auto-calibration, on demand calibration) may be useful overtime to recalibrate the sensor because the sensitivity m of the sensormay change over time (for example, due to maturation of the membranethat may increase or decrease the glucose and/or oxygen availability tothe sensor). However, the baseline shifts that have conventionallyrequired numerous and/or regular blood glucose reference measurementsfor updating calibration (for example, due to interfering species,metabolism changes, or the like) can be consistently and accuratelyeliminated using the systems and methods of the preferred embodiments,allowing reduced interaction from the patient (for example, requestingless frequent reference glucose values such as daily or even asinfrequently as monthly).

An additional advantage of the sensor of the preferred embodimentsincludes providing a method for eliminating signal effects ofinterfering species, which have conventionally been problematic inelectrochemical glucose sensors. Namely, electrochemical sensors aresubject to electrochemical reaction not only with the hydrogen peroxide(or other analyte to be measured), but additionally may react with otherelectroactive species that are not intentionally being measured (forexample, interfering species), which cause a change in signal strengthdue to this interference. In other words, interfering species arecompounds with an oxidation or reduction potential that overlap with theanalyte being measured. Interfering species such as acetaminophen,ascorbate, and urate, are notorious in the art of glucose sensors forproducing inaccurate signal strength when they are not properlycontrolled. Some glucose sensors utilize a membrane system that blocksat least some interfering species, such as ascorbate and urate.Unfortunately, it is difficult to find membranes that are satisfactoryor reliable in use, especially in vivo, which effectively block allinterferants and/or interfering species (for example, see U.S. Pat. No.4,776,944, U.S. Pat. No. 5,356,786, U.S. Pat. No. 5,593,852, U.S. Pat.No. 5,776,324, and U.S. Pat. No. 6,356,776).

The preferred embodiments are particularly advantageous in theirinherent ability to eliminate the erroneous transient and non-transientsignal effects normally caused by interfering species. For example, ifan interferant such as acetaminophen is ingested by a host implantedwith a conventional implantable electrochemical glucose sensor (namely,one without means for eliminating acetaminophen), a transientnon-glucose related increase in signal output would occur. However, byutilizing the electrode system of the preferred embodiments, bothworking electrodes respond with substantially equivalent increasedcurrent generation due to oxidation of the acetaminophen, which would beeliminated by subtraction of the auxiliary electrode signal from theglucose-measuring electrode signal.

In summary, the system and methods of the preferred embodiments simplifythe computation processes of calibration, decreases the susceptibilityintroduced by user error in calibration, and eliminates the effects ofinterfering species. Accordingly, the sensor requires less interactionby the patient (for example, less frequent calibration), increasespatient convenience (for example, few reference glucose values), andimproves accuracy (via simple and reliable calibration).

In another aspect of the preferred embodiments, the analyte sensor isconfigured to measure any combination of changes in baseline and/or insensitivity, simultaneously and/or iteratively, using any of theabove-described systems and methods. While not wishing to be bound bytheory, the preferred embodiments provide for improved calibration ofthe sensor, increased patient convenience through less frequent patientinteraction with the sensor, less dependence on the values/range of thepaired measurements, less sensitivity to error normally found in manualreference glucose measurements, adaptation to the maturation of themembrane over time, elimination of erroneous signal due to non-constantanalyte-related signal so interfering species, and/or self-diagnosis ofthe calibration for more intelligent recalibration of the sensor.

Preferably, a dual-electrode sensor's working electrodes E1, E2 shouldfunction identically, with identical sensitivity and/or baselinemeasurements. However, in some circumstances, small differences in theportions of the membrane at the first and second working electrodes canresult in slight differences in membrane sensitivities (m) and/or thebaselines (b) signal associated with the working electrodes. While notwishing to be bound by theory, it is believed that such smalldifferences can arise during manufacture, for example, when E1 and E2have one or more separate manufacturing steps. Additionally, thecompositions of the enzyme domains can be slightly different. Forexample, an E1 enzyme domain can be somewhat more hydrophilic than an E2enzyme domain manufactured without any added enzyme. In somecircumstances, certain characteristics of the blood samples (e.g., pH,certain medicaments in the host's circulatory system, temperature, pO₂)to which the sensor is exposed can, amplify the effects of thesedifferences. In some circumstances, these small differences (between E1and E2) can contribute to sensor inaccuracies. In preferred embodiments,such sensor inaccuracies can be avoided by use of a scaling factor (k)that is calculated by evaluating the signal response at each of theworking electrodes. In some embodiments, the scaling factor is measuredin vitro, prior to sensor implantation.

In one preferred embodiment, a scaling factor (k) is calculated byevaluating the signal response after at point at which substantially allof the analyte present in a blood sample should have been used up. FIG.3J is a graph that illustrates exemplary data collected upon exposure ofa dual-electrode continuous analyte sensor to a blood sample. The Y-axisrepresents the signal generated and the X-axis represents time. The topgraph is data generated by the plus-enzyme working electrode (e.g.,first working electrode, E1). The bottom graph is time-correspondingdata generated by the minus-enzyme working electrode (e.g.,non-enzymatic, second working electrode, E2). In general, when thesensor is exposed to a blood sample, the E1 signal will increase 1302until substantially all of the available analyte is used up (e.g., att1) by the enzyme at the plus-enzyme working electrode. In general, aswith most enzymes, when all of the substrate (e.g., analyte) is used up,the signal should plateau (e.g., line 1306). However, in spite of thelack of substrate (e.g., analyte) for the enzyme, the signal actuallycontinues to increase a small amount, as is shown by line 1308. Whilenot wishing to be bound by theory, it is believed that the signalincrease 1310 is due to signals caused by non-analyte-relatedelectroactive species, which diffuse through the membrane more slowlythan the analyte. This signal increase (line 1304) is also observed onthe non-enzymatic working electrode (e.g., E2). Accordingly, the signalresponse for E2, during the time period of t1 to t2, is the differencebetween lines 1305 and 1304. The scaling factor (k, also referred to asthe “buildup ratio”) can be determined by evaluating the signal responseat the two working electrodes (e.g., between t₁ and t₂) using theformula:

$k^{Sensor} = \frac{{Signal\_ response}_{Enzyme}}{{Signal\_ response}_{NoEnzyme}}$

Accordingly, for the exemplary data shown in FIG. 3J, the scaling factor(k) is equal to the ratio of the plus-enzyme signal response 1310 to theminus-enzyme signal response 1312. In a related embodiment, a scalingfactor can be calculated by evaluating data generated at the earlyportion of the curve, soon after the switch from a wash/referencesolution (e.g., saline, glucose, etc.) to blood, such as between about 2second and about 2 minutes after the switch from blood to non-bodilyfluid. The scaling factor can then be used to adjust the data (e.g.,calibrate) for differences in membrane sensitivities, thereby providingincreased sensor accuracy. In some embodiments, the dual-electrodesensor is a glucose sensor. However, dual-electrode sensors can beconfigured to detect other analytes as described elsewhere herein.

In some embodiments, the scaling factor can be determined by evaluatingthe signal responses of the first and second working electrodes E1, E2during exposure of the sensor to a non-bodily fluid (e.g., saline,reference/calibration solution, hydration fluid, wash fluid, nutritionalfluid, medicament, etc.). As described elsewhere herein, anintravascularly implanted dual-electrode analyte sensor can be washedand/or calibrated between exposures to blood samples. To measure thesignal response at the working electrodes, the non-bodily fluid can beheld stagnant (e.g., substantially not moving) for a period of time(e.g., from t1 to t2). Signal responses at the working electrodes,during the time period, can then be evaluated.

FIG. 3K is a graph that illustrates exemplary data received uponexposure of a dual-electrode sensor to a non-bodily fluid. The Y-axisrepresents signal generated at the working electrodes and the X-axisrepresents time. The top graph is data generated by the plus-enzymeworking electrode (e.g., first working electrode, E1). The bottom graphis time-corresponding data generated by the minus-enzyme workingelectrode (e.g., non-enzymatic, second working electrode, E2). Startingat t=0, the flow of fluid over the dual-electrode continuous analytesensor is stopped, such that the fluid is substantially stagnant (e.g.,not moving). At the first working electrode E1 (with enzyme), anincreasing signal is generated, as is represented by line 1314. Anincreasing signal is also generated at the second working electrode E2(no enzyme), as is illustrated by line 1316. The E1 signal response(1318) is the difference between lines 1315 and 1314 at t2. Similarly,the E2 signal response (1320) is the difference between lines 1317 and1316 at t2. While not wishing to be bound by theory, it is believed thatthe observed signal response is due to diffusion of non-analyte-relatedelectroactive species through the plus and minus enzyme membraneportions, which are then detected at the working electrodes. The sensorscaling factor can be calculated using the equation described above.

In some embodiments, to improve sensor accuracy, a scaling factor can becalculated by comparing the signal response of a test sensor(k^(TestSensor)) to the signal response of a “perfect sensor”(k^(PerfectSensor)), using the following formula:

${ScalingFactor} = \frac{k^{TestSensor}}{k^{PerfectSensor}}$

The signal response (k^(PerfectSensor)) for a perfect dual-electrodesensor (can be determined empirically by testing a plurality of sensorsin the laboratory, such as by using methods known in the art.

As described in more detail elsewhere herein, useful information (e.g.,sensitivity and/or scaling factor) can be extrapolated from periods inwhich the signal is transient, for example, during sensor break-inand/or during a period of signal artifact (e.g., noise). In someembodiments, the scaling factor is determined during electrochemicalbreak-in of the sensor. Additionally or alternatively, the scalingfactor is determined during a period of signal artifact, for example,wherein the flow of fluid across the sensor manipulated (e.g.,disrupted) intentionally and/or accidentally (and detected). In oneexemplary embodiment, the flow control device of the preferredembodiment is configured to jitter, reciprocate and/or dither in such away so as to more effectively wash the sensor; in this exemplaryembodiment, signal artifact is induced on the signal by the induced flowturbulence, which can be used to obtain useful information by transientanalysis of the signal.

Due to the kinetics of the signal during these transient events, a noiseamplitude can be determined for each of the first and second workingelectrodes of a dual electrode system, and the noise amplitude comparedto obtain a scaling factor. In one embodiment, the scaling factor isdetermined by using a residual analysis, wherein filtered (e.g.,smoothed) data is compared to raw data (e.g., in local and/or remoteelectronics) to obtain a signal residual. In one such embodiment, asignal residual is calculated as the difference between the filtereddata and the raw data. For example, at one time point (or one timeperiod that is represented by a single raw value and single filteredvalue), the filtered data can be measured at 50,000 counts and the rawdata can be measured at 55,500 counts, which would result in a signalresidual of 5,500 counts. In some embodiments, the residuals provide thenoise amplitude information, which can be compared to obtain a scalingfactor. However, in some embodiments, a stream of residuals (e.g.,individual time points during a kinetic period of the signal) for eachof the first and second working electrodes are averaged (e.g., using amoving average, or the like), and compared, to provide noise amplitudeinformation for each of the first and second working electrodes, whichcan be used to define a scaling factor.

In some embodiments, the manufacturer determines a baseline (e.g.,b_(offset)) and/or a scaling factor prior to sensor use in a host, suchas but not limited to testing in one or more reference solutions, suchas but not limited to an isotonic solution. The prospectively determinedbaseline (e.g., b_(offset)) and/or scaling factor can be included withthe sensor provided to the user, such as by providing a calibration codethat can be entered (e.g., manually) into the system electronics, thatcan be automatically detected by the system electronics upon sensorcoupling thereto (e.g., via a detectable memory), and the like, similarto the manufacturer-provided calibration codes for glucose test strips.

As a non-limiting example, in preferred embodiments, a system formeasuring an analyte, wherein differences in first and second workingelectrodes is accounted for, is provided. In this embodiment, the systemincludes a continuous analyte sensor, a vascular access device, areceiving module, and a processing module. The continuous analyte sensoris configured for exposure to a host's circulatory system in vivo, suchas via fluidly coupling with a vascular access device in fluid contactwith the host's circulatory system. The continuous analyte sensorincludes first and second working electrodes E1, E2. The first workingelectrode E1 is disposed beneath an enzymatic portion of a membranesystem, wherein the enzymatic portion includes an enzyme for detectingthe analyte. For example, if the analyte is glucose, the enzymaticportion includes GOX. If the analyte is cholesterol, the enzyme is acholesterol-metabolizing enzyme. The second working electrode E2 isdisposed beneath a non-enzymatic portion of the membrane system, whichincludes either no enzyme or an inactive form of the enzyme. Forexample, the enzyme can be inactivated by a variety of methods, such asdenaturing by heating, UV exposure, treatment with a protease or adenaturing chemical, and the like. In some embodiments, the enzyme layerof the membrane system over E2 (e.g., the electroactive surface)includes another protein, such as BSA or ovalbumin, which is notinvolved in the metabolism of the analyte.

The system includes a receiving module configured to receive the signalsfrom the working electrodes (e.g., a first signal from E1 and a secondsignal from E2). As described elsewhere herein, the first signal isassociated with both the analyte and non-analyte related electroactivecompounds; the second signal is associated with non-analyte relatedelectroactive compounds. The non-analyte related compounds have anoxidation/reduction potential that substantially overlaps with theanalyte's oxidation/reduction potential. Accordingly, if thedual-electrode sensor is configured to detect glucose, E1 detects asignal having components associated with glucose and non-glucose speciesthat have oxidation/reduction potentials that substantially overlap withthe oxidation and/or reduction potential of glucose (sometimes referredto herein as a first oxidation/reduction potential), and E2 detects asignal related to the non-glucose species that have oxidation/reductionpotentials that substantially overlap with the oxidation and/orreduction potential of glucose.

The system includes a processor module configured to and/or comprisingprogramming that processes the first and second signals and to estimatea scaling factor. As described herein, the scaling factor defines arelationship between the first and second working electrodes (e.g.,associated with the measured baseline of each first and second workingelectrodes). Preferably, the processor module processes the first andsecond signals using the scaling factor, to thereby obtain a signal(e.g., a glucose value) substantially without contribution due tonon-analyte related electroactive compounds. For example, wherein theequation b=kz defines the relationship (scaling factor (k)) between thebaseline (b) of the first (enzymatic) working electrode and the baselinez of the second (non-enzymatic) working electrode. A calibrationequation (y=mx+b) can be modified to include the scaling factor tocalibrate the sensor (y−kz=mx).

In some preferred embodiments, the system includes a flow control deviceis configured to meter a flow of a fluid through the vascular accessdevice. In some embodiments, the fluid is a bodily fluid and the flowcontrol device is configured to withdraw a sample of bodily fluid (e.g.,blood) from the host such that the sensor is contacted with the bodilyfluid. In a further embodiment, the processor module is configured toand/or comprises programming that compares steady-state information ofthe first signal and steady-state information of the second signal. Insome embodiments, the fluid is a non-bodily fluid and the flow controldevice is configured to hold the non-bodily fluid substantially stagnantduring a time period, as described herein. In preferred embodiments, theprocessor module is configured to and/or comprises programming thatcompares a signal increase on each of the first and second workingelectrodes during the time period during which the non-bodily fluid isheld stagnant, as described herein.

In preferred embodiments, a method for processing sensor data from adual-electrode continuous analyte sensor, including estimating a scalingfactor (k), is provided. The dual-electrode sensor, as described herein,is configured for in vivo exposure to a host's circulatory system. Thedual-electrode continuous analyte sensor is applied to the host, such asvia fluidly coupling the sensor to a fluid flow device. In someembodiments, the sensor is configured for insertion into a catheter oris a part of the catheter, as described above. In some embodiments, thesensor is part of a connecting device, such as a Leur lock, which isfluidly coupled to a catheter at a first end and to the rest of thefluid flow device (e.g., via IV tubing), such that blood samples can bewithdrawn and contacted with the sensor. After the sensor has beenapplied to the host, signals from the working electrodes can bereceived, as described elsewhere herein. A scaling factor, which definesa relationship between a the first and second working electrodes, can beestimated from the received signals, and then the scaling factor can beused to process the signals and thereby to obtain a signal substantiallywithout contribution due to non-analyte related electroactive compounds.In some embodiments, the scaling factor is determined while contactingthe sensor with a bodily fluid (see above), such as by comparingsteady-state information of the first signal and steady-stateinformation of the second signal. In some embodiments, the scalingfactor is determined while contacting the sensor with a substantiallystagnant non-bodily fluid, such as by comparing a signal increase oneach of the working electrodes during exposure to the substantiallystagnant non-bodily fluid.

While not wishing to be bound by theory, it is believed thatdetermination of a scaling factor as described herein provides a numberof advantages. First, sample collection/testing is alternated withcalibration and/or washing, sensor calibration is continuous andbiofouling is substantially reduced. Since there is little biofouling,the sensor functions more rapidly (e.g., T₉₀ is reached more rapidly).Since the sensor is continuously calibrated during use (e.g., such thatbackground is removed) the user receives more accurate glucoseinformation/values to be used in making therapeutic decisions. Thus, itis substantially easier and safer for the host to maintain tight controlover his or her glucose levels, which can result in a better quality oflife and reduced long-term diabetic complications.

In many circumstances, glucose sensors can be calibrated using dataprovided either by an analyte testing device separate from thecontinuous analyte sensor system. For example, points for a continuousglucose sensor, one or more reference data may be provided by testing ablood sample with a hand-held glucose meter or with an YSI glucose testdevice. However, in some preferred embodiments, a system, including acontinuous analyte sensor (single working electrode or dual workingelectrode), is configured to provide one or more data points, with whichthe continuous analyte sensor can be calibrated, without the use of aseparate (e.g., external to the system) device and/or testing ofreference fluids.

Accordingly, in preferred embodiments, the continuous analyte detectionsystem includes a continuous analyte sensor (e.g., described elsewhereherein) and a reference analyte sensor. The continuous analyte sensor isconfigured to detect a first signal associated with a test analyte and asecond signal is associated with a reference analyte. The referencesensor is configured to generate a reference signal associated with thereference analyte. The test analyte can be any analyte that the sensoris configured to continuously monitor in the host. For example, in somepreferred embodiments, the test analyte is glucose. The referenceanalyte is an analyte other than the test analyte, which issubstantially stable within the host. For example, in general, theconcentration of the reference analyte (e.g., in the host's circulatorysystem) does not fluctuate rapidly. In some preferred embodiments, thereference analyte is oxygen (O₂); however, a variety of other analytescan be used. The reference analyte selected is an analyte that can bemeasured by both the continuous analyte sensor and the reference sensor.

The continuous analyte sensor can be any type of continuous analytesensor, including a continuous analyte sensor having a single workingelectrode or dual-working electrodes. In some embodiments, thecontinuous analyte sensor is a single working electrode continuousanalyte sensor configured to detect glucose, and the first signal isassociated with glucose. In this embodiment, the working electrode isconfigured to detect the second signal (associated with the referenceanalyte). For example, in some embodiments, the sensor is configured togenerate a signal associated with glucose when a +0.6 mV potential isapplied to the sensor. In some circumstances, the sensor can detectanother analyte, if a different potential is applied thereto. Forexample, if a −0.6 mV potential is applied, the sensor can detect O₂.Accordingly, in some embodiment, the system is configured to detect bothglucose and O₂ (e.g., first and second signals) at the working electrodeof the continuous analyte sensor, by switching the potential applied tothe sensor. In some embodiments, the continuous analyte sensor includesan auxiliary electrode, which can be configured to detect the referenceanalyte (second signal), as described herein with reference to“transport-measuring” electrodes.

In other embodiments, the continuous analyte sensor is a dual-workingelectrode continuous analyte sensor configured to detect glucose, andthe first signal (detected by the working electrode disposed beneath anenzymatic portion of the membrane) is associated with glucose. In someembodiments, the system is configured to detect the second signal(associated with the reference analyte) using the dual-electrodesensor's first working electrode (E1, with enzyme) as described above.In other embodiments, the system is configured to detect the secondsignal (reference analyte) using the dual-electrode sensors secondworking electrode (E2, no enzyme), such as by applying a −0.6 mVpotential thereto. In this embodiment, the second signal associated withthe reference analyte should not be confused with the signal detected bythe second working electrode that is associated with non-analyte-relatedelectroactive species that have an oxidation/reduction potential thatsubstantially overlaps with the analyte's oxidation/reduction potential.For example, in some embodiments, the dual-electrode sensor isconfigured such that when a +0.6 mV potential is applied to the secondworking electrode (E2, disposed beneath a non-enzymatic portion of themembrane) the signal generated is associated with thenon-analyte-related electroactive species that have anoxidation/reduction potential that substantially overlaps with theanalyte's oxidation/reduction potential; then, when a −0.6 mV potentialis applied to the second working electrode, the second working electrodedetects the second signal (associated with the reference analyte).

In some embodiments, the continuous analyte sensor includes more thantwo working electrodes disposed beneath the membrane. In one exemplaryembodiment, the sensor includes a first working electrode E1 configuredto generate a signal associated with the analyte (the first signal), asecond working electrode E2 configured to generate a second signalassociated with the reference analyte, and a third working electrode E3configured to generate a signal associated with the non-analyte-relatedelectroactive species that have an oxidation/reduction potential thatsubstantially overlaps with the analyte's oxidation/reduction potential.In some embodiments, the sensor can include an additional workingelectrode (e.g., E4, E_(n)) configured to detect another referenceanalyte and/or to generate signals associated with non-analyte-relatedspecies that have oxidation/reduction potentials that overlap with thatof another analyte, the reference analyte, another reference analyte,and the like.

In preferred embodiments, the reference sensor is not disposed beneaththe analyte sensor's membrane and is configured to detect the referenceanalyte using any means known in the art, such as but not limited toelectrochemical, enzymatic, chemical, physical, immunochemical,radiometric, and the like. In some preferred embodiments, the referencesensor is an optical sensing apparatus configured to detect thereference analyte. For example, the reference sensor can be an opticalO₂ sensing apparatus configured to use one of a variety of opticaldetection methods known in the art and a described herein in the sectionentitled “Optical Detection.”

In preferred embodiments, the system is configured such that thecontinuous analyte sensor and the reference sensor are disposed in thesame local environment and are therefore simultaneously exposed to(e.g., contacted by/with) the sample (e.g., blood). For example, in someembodiments, the system can be configured such that the continuousanalyte sensor is a wire sensor configured to extend into a catheter,and the reference sensor comprises an optical fiber that is configuredboth to detect the reference analyte and to extend into a catheter suchthat the detecting portion of the reference sensor is adjacent to thesensing portion of the continuous analyte sensor. In another exemplaryembodiment, the continuous analyte sensor and the reference sensor aredisposed within a connector; such as described in the section entitled“Multi-sensor apparatus.” In still another exemplary embodiment, thecontinuous analyte sensor and the reference sensor are integrally formedon a vascular access device, such as on the in vivo portion of acatheter. For example, an optical fiber can be incorporated into the invivo portion of the catheter during manufacture (e.g., such as viainjection molding techniques known in the art) or by attaching theoptical fiber with an adhesive, and subsequent the deposition of thecontinuous analyte sensor electrodes to the exterior surface of the invivo portion of the catheter, as described herein.

In preferred embodiments, the system includes a processor moduleconfigured to and/or comprises programming that processes the secondsignal (associated with the reference analyte) and the reference signalto calibrate the first signal (associated with the analyte). Forexample, in some embodiments, the processor module uses the referencesignal, which is generated by a sensor outside the membrane, tocalibrate the second signal (generated under the membrane). Accordingly,shifts in baseline and/or sensitivity, which can arise over time duringuse of the sensor, are accounted for prior to calibration of the firstsignal (generated under the membrane). The processor configured to thencalibrate the first signal (analyte signal) using the calibrated secondsignal, which generates a first signal substantially without anon-analyte signal component (and substantially unaffected by shifts insensitivity (m) and/or baseline (b)).

As a non-limiting example, in one embodiment, the system includes acontinuous glucose sensor configured to detect a first signal associatedwith glucose and a second signal associated with O₂. The system alsoincludes an optical sensing apparatus configured to detect O₂. Thesystem is configured such that the glucose sensor and the optical O₂sensing apparatus can be exposed simultaneously to a sample. This methodfor calibration requires measurement of a second analyte that is alreadybeing monitored. For example, optical sensors are almost always used tomeasure O₂ in the host. In some embodiments, the glucose sensor's firstworking electrode generates both the analyte signal and the O₂ signal.In some embodiments, an electrode other than the first working electrode(e.g., a second or third working electrode) is configured to generatethe O₂ signal. Then the optical O₂ sensor can be used to calibrate theO₂ electrode (of glucose sensor system). Assuming there is a knownrelationship between the sensitivities of an electrode configured togenerate a glucose signal and an electrode configured to generate an O₂signal, then the sensor's glucose electrode can be calibrated by the O₂electrode.

While not wishing to be bound by theory, it is believed that an analytedetection system configured to calibrate the analyte signal using asecond/reference analyte provides a plurality of advantages. Primarily,calibration of a system of the preferred embodiments does not requireinput (manually or automatically) of reference data points from asecondary detection system (e.g., separate from the analyte detectionsystem), such as a hand-held glucose meter. Similarly, no special IVbag, mechanical components or dedicated IV lines are required. A widevariety of analytes can be detected by both electrochemical means and asecondary means, such as optical detection methods. All of theseadvantages conflate to provide highly accurate, “plug-and-play” stylecontinuous analyte detection system that is usable in a wide variety ofsettings.

Integrated Sensor System System Overview

In the hospital environment, such as in Intensive Care Units, patientscommonly have multiple access points to their circulatory systems, fordrug and fluid infusion, and for each blood sample collection. In suchsettings, a variety of analytes in the host's blood are regularlymonitored, by collection of a blood sample and sending the sample to anon-site laboratory for analysis. This system had serious drawbacks, suchas giving slow, non-continuous analyte monitoring results and requiringa lot of hospital staff attention. For example, tight control of glucoselevels is critical to patient outcome in a critical care medicalsetting, especially for diabetic hosts. Maintaining tight glucosecontrol with current technology poses an undue burden to medicalpersonnel, due to time constraints and the extensive patient contactrequired. Reducing medical staff workload is a key component ofimproving patient care in this setting. The preferred embodimentsdisclose systems and methods to automatically and continuously test hostanalytes at the bedside while reducing and/or minimizing staff-patientinteractions. Additionally, the preferred embodiments decrease testingintervals and improve sensor accuracy and reliability.

FIGS. 6 and 7 illustrate one preferred embodiment of the integratedsensor system 600 (e.g., for use at the bedside), which couples to theanalyte sensor 14 (e.g., a glucose sensor) and vascular access device 12(e.g., a catheter placed in a peripheral vein or artery) described above(see FIGS. 1A-1E), and which includes at least one fluid reservoir 602(e.g., a bag of calibration or IV hydration solution), a flow controldevice 604 (e.g., to control delivery of an infusion fluid 602 a fromthe reservoir to the host via the catheter), a local analyzer 608 and aremote analyzer 610. In some embodiments, the analyte sensor isconfigured to reside within the catheter lumen 12 a (see FIGS. 1A-1E).In some embodiments, the sensor is disposed within the catheter such thesensor does not protrude from the catheter orifice 12 b. In otherembodiments, the sensor is disposed within the catheter such that atleast a portion of the sensor protrudes from the catheter orifice. Instill other embodiments, the sensor is configured to move betweenprotruding and non-protruding configurations. The analyte sensor andvascular access device used in the integrated sensor system 600 can beany types known in the art, such as but not limited to analyte sensorsand vascular access devices described above, in the sections entitled“Applications/Uses” and “Exemplary Sensor Configurations.” Forconvenience, the vascular access device 12 will be referred to as acatheter herein. However, one skilled in the art appreciates that othervascular access devices can be used in place of a catheter.

In some embodiments, at least one electronics module (not shown) isincluded in the local and/or remote analyzers 608, 610 respectively, forcontrolling execution of various system functions, such as but notlimited to system initiation, sensor calibration, movement of the flowcontrol device 604 from one position to another, collecting and/oranalyzing data, and the like. In preferred embodiments, the componentsand functions of the electronics module can be divided into two or moreparts, such as between the local analyzer and remote analyzer, as isdiscussed in greater detail in the sections entitled “Local Analyzer”and “Remote Analyzer.”

In some embodiments, the flow control device 604 includes one or morevalves and is configured to control fluid delivery to the host andsample take-up (e.g., drawing blood back into the catheter until atleast the sensor's electroactive surfaces are contacted by the blood).In some embodiments, the sensor 14 dwells within the lumen 12 a of thecatheter 12, as described elsewhere herein. In some embodiments, whereinan internal calibration is performed, an infusion fluid (e.g.,calibration solution 602 a) flows over the indwelling sensor 14 and isinfused into the host. Generally, analyte in the solution 602 a can bemeasured when the sensor electroactive surfaces are in contact with thesolution 602 a. In some embodiments, the measurements of the solution602 a can be used to calibrate the sensor 14. After calibration, thesystem is configured such that a sample (e.g., blood or other bodilyfluid) contacts the sensor's electroactive surfaces (e.g., by drawingblood back into the catheter). When the sample contacts theelectroactive surfaces, the sample's analyte concentration can bedetected by the sensor 14. When a sample is drawn back, the sample canthen be returned to the host. In some embodiments, the integrated sensorsystem 600 cycles between calibration (e.g., measurement of a referencecalibration solution) and measurement (e.g., of a sample, such as blood,glucose concentration). In some embodiments, the system 600 continuesoperation in this cyclical manner, until the system 600 is eitherdisconnected from the host or turned off for a period of time (e.g.,during movement of the host from one location to another). For example,in one embodiment, the system 600 cycles between the calibration andmeasurement steps from about every 30 seconds or less to about every 2hours or more. In another embodiment, the system 600 cycles between thecalibration and measurement steps of from about every 2 minutes to aboutevery 45 minutes. In still another embodiment, the system 600 cyclesbetween the calibration and measurement steps from about every 1 minuteto about every 10 minutes. In some embodiments, the user can adjust thetime between steps. In some embodiments, the user can adjust the timebetween each step. In some embodiments, the system 600 can performadditional steps, such as but not limited to a flushing step, a keepvein open step (KVO), an extended infusion step, and the like. In someembodiments, the time is dependent upon sensors that detect a referencesolution (e.g., calibration solution) and/or sample (e.g., blood) at theelectroactive surfaces.

The integrated sensor system 600 of the preferred embodiments providesseveral advantages over prior art technology. Namely, in preferredembodiments, continuous analyte monitoring is enabled. When the analyteis glucose, continuous glucose monitoring enables tight glucose control,which can lead to reduced morbidity and mortality among diabetic hosts.Additionally, the medial staff is not unduly burdened by additionalpatient interaction requirements. Advantageously, there is no net sample(e.g., blood) loss for the host, which is a critical feature in someclinical settings. For example, in a neonatal intensive care unit, thehost is extremely small and loss of even a few milliliters of blood canbe life threatening. Furthermore, returning the body fluid sample to thehost, instead of delivering to a waste container greatly reduces theaccumulation of biohazardous waste that requires special disposalprocedures. The integrated sensor system components, as well as theiruse in conjunction with an indwelling analyte sensor, are discussed ingreater detail below.

Fluids

Referring to FIGS. 6 and 7, in preferred embodiments, the integratedsensor system 600 includes at least one reservoir 602 that contains aninfusion fluid 602 a, such as but not limited to reference (e.g.,calibration), hydration and/or flushing solutions. For simplicity, theinfusion fluid 602 a will be referred to herein as a solution 602 a.However, one skilled in the art recognizes that a wide variety ofinfusible fluids can be used in the embodiments discussed herein.

In some embodiments, the reservoir 602 includes a container such as butnot limited to an IV bag. In other embodiments, the reservoir 602 caninclude two or more IV bags, or any other sterile infusion fluidcontainer. In some embodiments, the reservoir 602 is a multi-compartmentcontainer, such as but not limited to a multi-compartment IV bag. If twoor more solutions 602 a (e.g., calibration solutions, flush solutions,medication delivery solutions, etc.) are used, the solutions 602 a canbe contained in two or more IV bags or in a multi-compartment IV bag,for example. In some embodiments, it is preferred to use a singlesolution 602 a. Use of a single solution 602 a for calibration, catheterflushing and the like simplifies the system 600 by reducing thecomplexity and/or number of system 600 components required for system600 function. In some embodiments, two or more solutions 602 a arepreferred, and can be provided by a multi-compartment IV bag or two ormore separate reservoirs 602 (e.g., two or more bags, each containing adifferent solution 602 a). Advantageously, use of multiple solutions 602a can increase system functionality 600 and can improve sensor accuracy.

Any infusion fluid (e.g., solution 602 a) known in the art can be usedin conjunction with the present system 600. In some embodiments, thesolution 602 a is an analyte-containing solution that can be used as areference or standard for sensor 14 calibration (generally referred toas a reference and/or calibration solution in the art). In someembodiments, a solution 602 a can be used as a flushing solution, towash a sample off the sensor 14 and out of the catheter 12. In someembodiments, two or more solutions 602 a (e.g., having different analyteconcentrations) can used to provide two or more calibrationmeasurements. In one exemplary embodiment, the analyte sensor 14 is aglucose sensor, and the solution 602 a contains dextrose or glucose at aconcentration of from about 0 mg/dl to about 400 mg/dl. In preferredembodiments, the solution 602 a contains from about 75 mg/dl to about200 mg/dl glucose. In more preferred embodiments, the solution 602 acontains from about 100 mg/dl to about 150 mg/dl glucose. In someembodiments, the solution 602 a is an isotonic saline solution. In someembodiments, the solution 602 a contains a sufficient concentration ofan anticoagulant to substantially prevent blood clotting in and/or nearthe catheter 14. In some embodiments, the solution 602 a contains asufficient concentration of or antimicrobial to substantially preventinfection in and/or near the catheter. In one exemplary embodiment, thereservoir 602 is a 500 ml bag containing a sterile solution 602 aincluding 0.9% sodium chloride in water (e.g., normal saline), 2 IU/mlheparin and 100 mg/dl dextrose. In another exemplary embodiment, thereservoir 602 is a 500 ml bag containing heparinized saline.

In some embodiments, one, two or more solutions 602 a can be used inconjunction with the integrated sensor system 600. For example, in someembodiments, two or more calibration solutions 602 a (e.g., solutionswith different analyte concentrations) can be used. In one preferredembodiment, the analyte sensor 14 is a glucose sensor and thecalibration solution 602 a includes a glucose concentration of from 0mg/dl to about 300 mg/dl or more. In one exemplary embodiment, a singlecalibration solution 602 a (e.g., having a 100 mg/dl glucoseconcentration) can be used. In another exemplary embodiment, twocalibration solutions 602 a (e.g., having 100 mg/dl and 0 mg/dl glucoseconcentrations) can be used. In other exemplary embodiments, threecalibration (e.g., 0 mg/dl glucose, 75 mg/dl glucose and 300 mg/dlglucose) solutions 602 a can be used. In still other embodiments, morethan three calibration solutions 602 a can be used. In addition tocalibration solutions 602 a, non-calibration solutions 602 a can be usedin conjunction with the integrated sensor system 600, such as but notlimited to intravenously administered drugs, insulin, enzymes,nutritional fluids, and the like.

In some circumstances, it is preferred to infuse two or more differentsolutions (e.g., provided in separate IV bags) to the host through thesame IV tubing, while not mixing the solutions in the tubing. In someembodiments, the system is configured to infuse two or more separatesolutions without mixing by inserting (e.g., injecting) a small oxygenbubble between the two different solutions as they are released from theIV bags (e.g., when switching from one solution to the other). In someembodiments, alternative gases or a small amount of glycerin issubstituted for oxygen. The size of the bubble necessary to separate thetwo fluids depends in part on the inner diameter of the tubing. Forexample, a smaller bubble is required when smaller internal diametertubing is used than when larger internal diameter tubing is used. Insome embodiments, the bubble has a volume of from about 1, 3, 5-μl toabout 6, 8, 10, 15, 20, 25 or 30-μl or greater. In some embodiments, thebubble is injected at the flow control device. In some embodiments, thesystem includes a bubble injector.

The solution 602 a can be provided to the user in a variety of ways,depending upon local hospital protocol and/or physician preference. Insome embodiments, the solution 602 a is supplied pre-mixed (e.g., an IVbag containing sodium chloride, dextrose and heparin), such that fluidreservoir 602 can be connected to an infusion set and infused into thehost with minimal effort. In other embodiments, one or more of thesolution components 602 a can be provided separately, such that thefinal solution 602 a is prepared at the host's bedside, at the nurse'sstation or in the hospital pharmacy, for example. In one exemplaryembodiment, the solution 602 a can be provided to the medical staff as akit including a bag of sterile solution (e.g., water) and injectablesodium chloride, dextrose and heparin aliquots of sufficient quantity toprepare the final solution 602 a. The solution 602 a can be mixed at thebedside or at a location remote from the host, and then applied to thehost and to the integrated sensor system 600. In some embodiments, thereservoir 602 is a 500 ml or 1000 ml bag containing a sterile solutionof heparinized saline and 100 mg/dl, 150 mg/dl or 200 mg/dl glucose.

In various preferred embodiments, the solutions 602 a are administeredwith standard IV administration lines, such as those commonly usedtoday, such as a sterile, single-use IV set, referred to herein astubing 606. In some embodiments, the tubing 606 can be provided with thesolution(s) 602 a. While in other embodiments, the tubing 606 can beprovided separately from the solution(s) 602 a or other systemcomponents. Additional system 600 components that can be provided withthe solution(s) 602 a include but are not limited to a sensor 14, acatheter 12, tubing 606, a local analyzer 608, wires and/or cables forhard-wire connections between system components, and the like.

In some embodiments, multiple solutions 602 a can be infused through amulti-lumen catheter 12, such as but not limited to a two-lumen orthree-lumen catheter. In some embodiments, the sensor 14 is disposed inone of the catheter's lumens 12 a, through which one or more calibrationsolutions 602 a can be passed, while other fluids (e.g., hydrationfluids, drugs, nutritional fluids) to be delivered to the patient areinfused through the other catheter 12 lumens 12 a (e.g., second, thirdor more lumens).

In some embodiments, the reservoir 602 is held by a support 612. Thesupport 612 can take many forms, such as an elevated support. In someembodiments, the support 612 is an IV pole, such those commonly used inmedical care facilities. In some embodiments, the reservoir 602 issuspended on the support 612, and the height of the reservoir 602 can beadjusted (e.g., raised or lowered) to modulate solution 602 a dischargefrom the reservoir 602.

In some embodiments, the reservoir 602 and solution 602 a can beprovided with one or more system 600 components, such as in a kit. Inone exemplary embodiment, a kit including the components to mix thesolution 602 a can include an analyte sensor 14 and a standard infusionset (e.g., catheter 12, cannula, IV tubing 606, etc.). In otherembodiments, a kit can include a premixed solution 602 a, with ananalyte sensor 14. In various embodiments, a kit can containinstructions for use, such as for mixing the solution 602 a and applyingit to the integrated sensor system 600. Advantageously, providing eithera pre-mixed solution 602 a or solution components with one or moresystem 600 components (e.g., sensor 14, catheter 12, tubing 606, localanalyzer 608) can increase efficiency of medical care and provide easeof use to the nursing staff.

Flow Regulators

Still referring to FIGS. 6 and 7, in some embodiments, a flow regulator602 b controls the solution 602 a flow rate from the reservoir 602 tothe flow control device 604, which is described below. A variety of flowregulators can be used with the preferred embodiments, including but notlimited to pinch valves, such as rotating pinch valves and linear pinchvalves, cams and the like. In one exemplary embodiment, the flowregulator 602 b is a pinch valve, supplied with the IV set and locatedon the tubing 606 adjacent to and below the drip chamber. In someembodiments, a flow regulator 602 b controls the flow rate from thereservoir 602 to a flow control device 604, which is described in thesection entitled “Flow Control Device.” In some embodiments, a flowregulator is optional; and a flow control device 604 controls the flowrate (e.g., from the reservoir 602 to the catheter 14, describedelsewhere herein).

Flow Control Device

In preferred embodiments, the integrated sensor system 600 includes aflow control device 604. In some embodiments, the flow control device604 is configured to regulate the exposure of the sensor 14 to thesolution 602 a and to host sample (e.g., blood or other bodily fluid).In some embodiments, the flow control device 604 can include a varietyof flow regulating devices, such as but not limited to valves, cams,pumps, and the like. In one exemplary embodiment, the flow controldevice 604 includes a simple linear pinch valve. In another exemplaryembodiment, the flow control device 604 includes two or more linearpinch valves. In another exemplary embodiment, the flow control device604 includes one or more non-linear pinch valves. In another exemplaryembodiment, the flow control device 604 includes a global valve. Instill another exemplary embodiment, the flow control device 604 includesa gate valve, such as but not limited to a rising stem ornon-rising-stem valve. In another exemplary embodiment, the flow controldevice 604 includes a butterfly valve or a ball valve. In still anotherexemplary embodiment, the flow control device 604 includes a pump, suchas but not limited to volumetric infusion pumps, peristaltic pumps,piston pumps and syringe pumps. In still other exemplary embodiments,the flow control device 604 can be configured to vary the pressure atthe reservoir 602, such as but not limited to a pressure cuff around anIV bag and/or raising/lowering the reservoir adjust head pressure. Insome embodiments, the flow control device 604 includes a gravity-fedvalve. In still other embodiments, the flow control device 604 isconfigured to use flow dynamics at the catheter 12, to regulate exposureto the sensor to solution or sample, as described elsewhere herein.Although some exemplary glucose sensors are described in detail herein,the system 600 can be configured to utilize a variety of analyte sensorsincluding a variety of measurement technologies, such as enzymatic,chemical, physical, electrochemical, spectrophotometric, polarimetric,calorimetric, radiometric, and the like.

Referring now to a preferred embodiment wherein the sensor is anenzyme-based sensor, it is known to those skilled in the art that therate of an enzymatic reaction is temperature dependent. Depending uponthe enzyme, temperature reductions generally slow enzymatic reactionrates; temperature increases generally increase reaction rates. Sincethe analyte sensors 14 described in the preferred embodiment hereindepend upon an enzyme (e.g., GOX) to detect the analyte (e.g., glucose)temperature changes during sensor calibration can result in artifacts onthe sensor signal. For example, if the solution 602 a temperature isreduced (relative to body temperature), the enzymatic reaction willproceed at a reduced rate (relative to the rate at body temperature),causing the solution's analyte concentration to appear artificially low,which can result in improper sensor calibration. In some circumstances,changes in the relative temperatures of the area of the host's bodysurrounding the sensor (e.g., the blood contacting the sensor and theflesh surrounding the implanted sensor) and of the solution 602 a can becaused by the host moving the implant site, covering (or uncovering) animplant site with a blanket, application of a heating pad or ice to theimplant site, and the like. In some circumstances, a high flow rate cancause large temperature fluctuations when the sensor is alternatelyexposed to blood and solution 602 a. For example, if the flow rate issufficiently slow, the infusion fluid 602 a can be sufficiently warmedby the body before it contacts the sensor; thus the calibrationmeasurements taken will be made at a temperature substantially similarto the temperature with the test measurements are taken in blood. If theflow rate is too fast, the infusion fluid 602 a will not warm upsufficiently, and the temperature will be too cold when the calibrationmeasurements are taken, which can lead to improper sensor calibration.An improperly calibrated sensor can aberrantly measure the analyteconcentration in the sample (e.g., blood from the host). Aberrantreadings of sample analyte concentration can lead to improper treatmentdecisions by the medical staff and/or the host. The effects oftemperature on enzymatic reaction rates can be mathematically describedusing a temperature coefficient. Signal artifacts caused bytemperature-related reductions in enzyme reaction rate are referred toherein as temperature coefficient artifacts.

Generally, the host tissue in which the catheter 12 has been implantedsurrounds an in vivo portion of the catheter 12. In preferredembodiments, the flow control device 604 is configured to pass thesolution 602 a through the catheter 12 at a rate such that thesolution's temperature substantially equilibrates with the temperatureof the surrounding host tissue. In one exemplary embodiment, the flowcontrol device 604 maintains a flow rate of from about 0.9, 0.8, 0.7,0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03,0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002 or0.001 ml/min or less to about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,1.8, 1.9 or 2.0 ml/min or more. In one exemplary embodiment, the flowrate is from about 0.5 μl/min or less to about 1.5 ml/min or more. Inone preferred embodiment, the flow rate is from about 1 μl/min to about1.0 ml/min. In one exemplary preferred embodiment, the flow rate is fromabout 0.01 ml/min to about 0.2 ml/min. In another exemplary preferredembodiment, the flow rate is from about 0.05 ml/min to about 0.1 ml/min.Advantageously, since the flow control device 604 infuses the solution602 a at a rate sufficient to allow substantial temperatureequilibration with the surrounding tissue, sensor 14 accuracy isimproved and the integrated sensor system 600 has substantially notemperature coefficient artifacts.

In some alternative embodiments, a faster flow rate that does not allowfor temperature equilibration is preferred. In such circumstances,measurement inaccuracies due to temperature coefficient can be generallyeliminated mathematically using b_(offset) and the calibration methodsdescribed in the section entitled “Systems and Methods for ProcessingSensor Data.”

In some embodiments, sample is taken up into the same catheter lumen 12a through which the solution 602 a is infused into the host (describedelsewhere herein). Thus, it is preferred that mixing of the sample andthe solution 602 a is prevented. Similarly, it can be advantageous todetect when the sensor 14 is in contact with undiluted sample and/orundiluted solution. In some preferred embodiments of the integratedsensor system 600, the flow control device 604 is configured tosubstantially prevent mixing of two or more fluids, such as but notlimited to the solution 602 a and a host sample (e.g., blood). Inpreferred embodiments, mixing can be substantially prevented by acombination of factors, including specific gravity and flow rate. It isknown that two solutions with different specific gravities tend not tomix, provided that the fluids are moved at a sufficiently slow rate(e.g., flow rate). Human whole blood has a specific gravity of about1.05-1.06, while an infusion solution of 5% dextrose and 0.225% NaCl hasa specific gravity of about 1.0189. Due to the difference in specificgravities, a blood sample and the solution 602 a tend to resist mixingwithin the tubing 606 when the flow rate is sufficiently slow. Inpreferred embodiments, the sample and the solution 602 a are movedwithin the catheter lumen 12 a at a rate such that substantially nomixing occurs therebetween. In some embodiments, the flow rate is fromabout 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07,0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005,0.004, 0.003, 0.002 or 0.001 ml/min or less to about 1.0, 1.1, 1.2, 1.3,1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 ml/min or more. In some embodiments,the flow rate is from about 0.01 ml/min to about 1.0 ml/min. In oneexemplary embodiment, the flow rate is from about 0.02 ml/min to about0.35 ml/min. In another exemplary embodiment, the flow rate is fromabout 0.02 ml/min to about 0.2 ml/min. In yet another exemplaryembodiment, the flow rate is from about 0.085 ml/min to about 0.2ml/min.

In preferred embodiments, the flow control device 604 can include avariety of fluid flow-regulating devices known in the art. In someembodiments, the flow control device 604 includes one or more valves,such as but not limited to linear and non-linear roller valves, linearand non-linear pinch valves, bi-directional valves (either linear ornon-linear), peristaltic rollers, cams, combinations thereof, and thelike. In some other embodiments, the flow control device 604 isconfigured to generate sufficient “head pressure” to overcome the host'sblood pressure such that the solution 602 a is infused into the host ata controlled rate; this can include elevating the fluid reservoir 602(e.g., gravity fed) and using a valve to control the fluid flow rate outof the reservoir 602 and into the host. In one exemplary embodiment, thefluid flows at a maximum rate (e.g., about 6.25 ml/hr, 0.1 ml/min) suchthat a maximum fluid volume of about 150 ml/day can be infused into thehost, however ranges much higher and/or lower can be implemented withthe preferred embodiments.

In one exemplary embodiment, the flow control device 604 is a rotatingpinch valve that has first and second positions. The valve can movebetween the two positions, for example, backward and forward, andthereby move fluids in and out of the catheter, as described in thesection entitled “Flow Control Device Function.” Namely, solution 602 acan be moved from the reservoir 602, over the electroactive surfaces ofthe sensor 14 and into the host; and sample can be drawn up from thehost, to cover the electroactive surfaces of the sensor 14, and thenpushed back into the host, by movement of the valve between the firstand second positions.

In one exemplary embodiment, the flow control device includes a rotatingpinch valve as described with reference to FIGS. 8A through 8C. AlthoughFIGS. 8A to 8C describe one implementation of a rotating pinch valvethat can be implemented with the sensor system, some alternativesinclude rotating pinch valves with multiple pinch surfaces, for examplearound the circumference of the rotatable axle (FIGS. 8A-8C, 804), whichenables the use of one valve for multiple infusion fluids (e.g., usingmultiple IV lines).

In some embodiments, the flow control device 604 includes one or morecams that regulate the flow rate. In one embodiment, the flow controldevice 604 includes a plurality of fixed orifices, which are opened andclosed by the cams. As the cams are rotated, the flow increases and/ordecreases in response. In one exemplary embodiment, the flow controldevice 604 includes three openings and three cams that mate with theopenings (one cam per opening); fluid can flow through each opening at agiven rate, X ml/min. Accordingly, when the cams close all threeopenings, flow is stopped. When one of the openings is opened, the fluidflows at X ml/min. If two openings are opened, fluid flows at 2X ml/min.Similarly, when the three openings are opened (e.g., by turning the camssuch that they no longer close the openings), the fluid flows at 3Xml/min.

In another example, the flow control device 604 includes a plurality ofcams and an equal plurality to tubes 606 passing through the cams, suchthat each cam can pinch closed the tube 606 that passes through it. Inan exemplary embodiment, the cams are arranged such that they pinch androll the tubing 606, such that fluid is pushed into the host and sampletaken up at pre-determined rates and times. For example, the flowcontrol device 604 can include two cams, each having a tube 606 threadedtherethrough. The cams are arranged such that each cam pinches and rollsthe tubing 606 passing therethrough to push fluid into the host at oneor more rates and to take up a blood sample.

In yet another example, the flow control device includes a rotating ballvalve controlled by a motor, wherein the direction of the ball valve canbe utilized to control a variety of functions, such as flow direction ofthe fluid.

As described in related herein, the sensor can be calibrated using morethan one reference/calibration solution. For example, in someembodiments, the system is configured to calibrate using two referencesolutions. In some embodiments, two solutions are used by metering theflow of one solution with the flow control device and intermittentlystopping and intermittently manually injecting the second solution suchthat the solution contacts the sensor a sufficient period of time forcalibration measurements to be taken. However, in preferred embodiments,the flow control device is configured to automate such “intermittent”calibrations (e.g., instead of manually injecting the calibrationsolution into the tubing) by actuating a secondary valve in atime-dependent manner, wherein the secondary valve in configured tometer the second calibration solution. The secondary valve can take on avariety of configurations, such as but not limited to a pinch valve, aratchet valve, a cam, locking bearings or a ball valve (within thetubing).

As a non-limiting example, the secondary valve is a pinch valve thatincludes a ratcheting disk attached to the front of the flow controlvalve (e.g., via an axle), first and second arms, and includes a pinthat can engage the tip of the second arm. In some preferredembodiments, the first and second arms are connected to each other by ajoint, which includes a biasing means, such as a torsional spring, thatpushes the second arm toward the ratcheting disk. The joint includes astop pin, which limits the distance the second arm can move away fromthe ratcheting disk. The first arm includes a detent (e.g., a finger)that is pressed into the tubing (threaded through the flow controldevice) by another biasing means configured to push the first arm towardthe ratcheting disk. Accordingly, in some embodiments, when the flowcontrol device rotates in the first direction the ratcheting disk is notengaged, and the first arm pinches the tube closed. In otherembodiments, when the flow control device rotates in the firstdirection, the disk rotates with the flow control device such that thetip of the second arm rides up and over the pin of the secondary valve.When the flow control device rotates in the second direction, it isconfigured to engage the ratcheting disk and has two positions. As theflow control device rotates to the first position, blood is taken upinto the catheter. At this point, the flow control device is configuredto reverse and rotate in the first direction. However, a portion of thetime, the flow control device rotates to the second position. As theflow control device rotates to the second position, the ratcheting diskremains engaged and the disk rotates far enough that the pin (on thedisk) engages the tip of the second arm. Accordingly, the second arm ispushed away from the flow control device. The continued movement of thesecond arm is prevented by the stop pin. Since the second arm mustcontinue to move away from the flow control device/ratcheting disk, thefirst arm is engaged by the second arm, and the entire structure ispushed away from the flow control device. Accordingly, the pinch on thetubing (e.g., by the detent) is relieved and the fluid in the tubing canflow. After a desired amount of fluid has flowed through the tubing, thepinch of the tubing (by the detent) is reapplied, by moving the flowcontrol device/ratcheting disk in the first direction.

As another non-limiting example, in some embodiments the flow controldevice includes a cam configured to control the pinching and un-pinchingof the tubing. For example, a cam (e.g., weighted) is attached to theflow control device or another structure (e.g., a ratcheting disk)attached to the flow control device. The tubing is compressed (pinched)by a detent on an arm. The arm has a joint and is biased towards theflow control device via a biasing means. At desired time points, theflow control device is configured to move the cam to a second position(e.g., 180°), such that the arm is pushed upward (e.g., by the cam) andthe pinch of the tubing is relieved. When the pinch of the tubing isrelieved, the solution can flow through the tubing. The flow controldevice then returns the cam to its first position, so that the tubing isrecompressed (pinched) and fluid flow is stopped.

In some embodiments, an electronics module (not shown) is incorporatedinto the flow control device 604, to provide local control over flowcontrol device function; in these embodiments, the flow control devicefunction can be transmitted to the local and/or remote analyzer forprocessing. In other embodiments, a remote analyzer 610 and/orelectronics module, such as but not limited to a computer system,controls the flow control device 604. System 600 components thatregulate the flow control device 604 are discussed in greater detailelsewhere herein.

In a further embodiment, the flow control device 604 is a computercontrolled rolling pinch valve that acts on the exterior of steriletubing 606 in order to control the flow rate of a solution 602 a from anelevated fluid reservoir 602 into the host. In preferred embodiments,the flow control device 604 is configured to pinch and roll a smallvolume of tubing 606 such that a sample of host blood is drawn up intothe catheter 12 (e.g., with a sensor 14 disposed therein) for analytemeasurement, and to then push the sample back into the host with asolution (e.g., the calibration solution 602 a). In general, the flowcontrol device 604 is configured to oscillate between drawing up a bloodsample and allowing flow of the calibration solution 602 a at apredetermined rate. In some embodiments, the flow control device 604includes at least one “hard stop” that ensures that the flow controldevice 604 does not move to a position that could endanger and/or injurethe host, such as by draining the IV bag 602 of fluid 602 a orinappropriately (e.g., excessively) withdrawing blood, for example.

Tubing and Catheter

Referring again to FIGS. 6 and 7, in preferred embodiments, theintegrated sensor system 600 includes tubing 606 (e.g., sterile tubingconfigured for use in intravascular fluid infusion) and a catheter 12,to deliver the solution 602 a from the reservoir 602 to the host.Generally, the tubing 606 and catheter 12 are sterile, single usedevices generally used in medical fluid infusion, and may be referred toas an “infusion set.” An infusion set may include additional components,such as but not limited to a cannula or needle for implanting thecatheter, sterilization fluid (e.g., on a gauze pad) for cleaning and/orsterilizing the insertion site (e.g., the host's skin), tape, gauze, andthe like. IV tubing is available in a variety of sizes andconfigurations, which find use in the preferred embodiments. Forexample, the tubing can be any size internal diameter, such as fromabout 0.5 mm to about 5 mm internal diameter. In various embodiments,the tubing can include a drip chamber and/or one or more access devices,such as but not limited to stopcocks, diaphragms and the like.

Catheters 12 are available in a variety of sizes and configurations.Catheters 12 for use in conjunction with an analyte sensor 14 aredescribed in detail, elsewhere herein. Briefly, the catheter 12 can beany single- or multi-lumen catheter having a straight or divided tubingconnector (e.g., straight-through, single shut off, double shut off,non-spill couplings, valves, T-connectors, Y-connectors, X-connectors,pinch clamps, Leur locks, back-flow valves, and the like). In someembodiment, the catheter is configured for insertion into the venousside of the host's circulatory system. In other embodiments, thecatheter is configured for insertion into the arterial side of thehost's circulatory system, into either a peripheral or a central artery.In some embodiments, the catheter 12 is configured with an integrallyformed sensor 14. In alternative embodiments, a non-integral sensor 14is configured for insertion into the catheter 12 after catheterinsertion. In some embodiments, the catheter 12 is a single lumencatheter that is configured for infusion of a fluid.

In another embodiment, the catheter includes at least two lumens (e.g.,a dual-lumen catheter), wherein each lumen includes an orificeconfigured and arranged for fluid communication with the bodily fluid ofthe host. In some embodiments, the first lumen is configured for fluidinfusion and the second lumen is configured for insertion of an analytesensor. In preferred embodiments, the orifice of the second lumen islocated more proximal to the second end of the catheter (e.g., thecatheter hub) than the first lumen orifice, such that a bodily fluiddrawn back into the second lumen is substantially undiluted by a fluidinfused through the first lumen. Accordingly, a sample substantiallyundiluted by fluid being infused into the host can be drawn back fortesting by the analyte sensor located in the second lumen. In thisembodiment, the catheter is no longer a “dedicated line” that isdedicated to the analyte sensor. In some embodiments, the catheterincludes three or more lumens. During insertion, a cannula or needle canbe inserted into one of the catheter's lumens, such that the catheter issubstantially supported during the insertion process. For example, insome embodiments, the sensor and dual-lumen catheter can be provided tothe user with a cannula pre-inserted into the first lumen and the sensorpre-inserted into the second lumen. After insertion, the cannula isremoved (the sensor remains in the second lumen) and IV tubing isconnected to the catheter hub. In some embodiments, the catheter, suchas but not limited to a dual lumen catheter, is formed from an extrudedpolymer containing an amount of Ag and/or AgCl such that the catheteritself functions as a reference electrode.

In some preferred embodiments, an indwelling sensor 14 is disposedwithin the catheter's lumen 12 a. In some embodiments, the catheter 12and sensor 14 are provided to a user together. In other embodiments, thecatheter 12 and sensor 14 are supplied separately. In an alternativeembodiment, the catheter 12 is a multi-lumen catheter configured forinfusion of two or more solutions. In preferred embodiments, a sensor 14is disposed within one of the catheter's multiple lumens 12 a. Forexample, a calibration solution 602 a (e.g., 100 mg/dl glucose insaline) can be infused through the lumen 12 a in which the sensor 14 isdisposed, while a hydration fluid (e.g., including a medication) can beinfused through a second lumen. Advantageously, a dual lumen catheter 12allows non-interrupted system use while other fluids are concurrentlyprovided to the host.

In some embodiments, only the working electrode(s) of the sensor 14 aredisposed within the catheter lumen 12 a and the reference electrode isdisposed remotely from the working electrode(s). In other embodiments,the sensor 14 is configured to intermittently protrude from the catheterlumen 12 a.

Referring now to FIGS. 10A-10D, in some embodiments, the flow controldevice and the IV tubing (e.g., the tubing set) are configured andarranged to releasably mate in a specific orientation. In someembodiments, the flow control device (e.g., the valve 604) and thetubing (referred to herein as a “tubing assembly” 606 a or a tubing set)are configured and arranged for uni-directional tubing installation(e.g., the tubing can be installed in only one direction). For example,the tubing assembly shown in FIGS. 10A-10D includes first and secondconnector ends 606 c, 606 d joined by a central portion of tubing 606 b.The central portion of tubing is sufficiently elastic that the tubingassembly can be stretched during installation into the valve. Forexample, the tubing assembly is held by the first and second ends 606 c,606 d during insertion into grove 803 of the valve. After the tubing isinstalled in the groove, the first and second ends are released,allowing the central portion to relax into a less-stretchedconfiguration. In some embodiments, the valve and/or tubing (e.g., thecentral portion) are configured and arranged such that the tubing is ina stretched state (e.g., elongated configuration) after installation.For example, the tubing can be slightly shorter than the distance fromone end of the valve to the other (e.g., the longitudinal length of thegroove). In some embodiments, the tension created by the remainingstretch in the central portion helps to hold the tubing assembly inplace during valve operation. Advantageously, uni-directional tubinginstallation can enable alignment of tubing components with specificvalve components, such that the aligned tubing and valve components canfunction together, such as described in the section entitled “Free FlowMitigation.”

In further embodiments, the valve and tubing (e.g., tubing assembly 606a) are configured and arranged to form a mechanical interlock whenmated. Advantageously, the mechanical interlock can reinforce and/orenable uni-directional tubing installation and/or help to maintain theinstallation of the tubing within the valve during valve operation. Themechanical interlock includes releasably engageable first and secondportions; namely, the valve comprises the first portion 809 (describedelsewhere herein) of the mechanical interlock and the tubing assemblycomprises the second portion (e.g., the second end 606 d of the tubingassembly 606 a) of the mechanical interlock. For example, in FIGS. 10Aand 10B, the bottom portion 606 d of the tubing assembly 606 a isconfigured as a male connector (e.g., including wings, fins, detents,fingers, etc.) configured to releasably mate with a femaleinterconnection 809 on the valve. For example, in the embodimentillustrated in FIG. 10A, the bottom portion 606 d of the tubing assemblyincludes a male interconnection (e.g., a key) having a rectangular bodyand an optional female portion of a Leur connector (e.g., for releasablymating with the male Leur connector of IV tubing); the valve'sinterlocking female interconnection (e.g., a lock) includes arectangular receptacle sized to receive the male interconnection,including a cylindrical indentation (e.g., a concave groove or well)sized and/or shaped to receive the optional Leur connector of the bottomportion. As another example, in the embodiment illustrated in FIG. 10B,the bottom portion 606 d of the tubing assembly includes fins havingcurved edges. Advantageously, the mechanical interlock, of the tubingassembly and the valve, prevents twisting (e.g., rotational movement) ofthe tubing assembly within the valve.

In some embodiments, the configuration of an interconnection (e.g., themale interconnection of the tubing assembly and/or the femaleinterconnection of the valve) is associated with a specific flowprofile. For example, a first interconnection configuration isassociated with a first flow profile; a second interconnectionconfiguration is associated with a second flow profile; and so on. In afurther embodiment, the interconnection and/or flow profile isassociated with a specific system configuration, such as for use in aspecific circumstance. For example, the system can be configured foruses in pediatric and/or adult hosts. Each type of host has a set ofrequirements associated with the system configuration. For example, apediatric host is much smaller than an adult host, and thus may requirea smaller catheter/fluid coupler and analyte sensor and slower infusionrelative to an adult host. In some embodiments, the system is configuredto recognize an interconnection (e.g., the configuration) and to use(e.g., program, select) the flow profile associated with the recognizedinterconnection. In some embodiments, the interconnection is mechanical.In other embodiments, the interconnection includes an electroniccomponent, such as but not limited to an RFID chip located in the tubingassembly (e.g., in the male interconnection of the mechanical interlock)that is detected by the flow control device.

As is described elsewhere herein, the valve is configured and arrangedfor at least two fluid flow positions, namely a gravity flow (alsoreferred to as free flow) position and a controlled flow position. Forexample, in some embodiments, the valve is configured and arranged suchthat the tubing is substantially straight in the gravity flow positionand the tubing is substantially non-linear in the controlled flowposition. In general, the position of the valve, including its directionand rate of movement, is associated with (e.g., corresponds to) the flowposition, which in turn is associated with (e.g., corresponds to) a flowrate. FIG. 10C illustrates the gravity flow valve position, whichcorresponds to a valve position in which the valve is substantially open(e.g., the tubing 606 b of the tubing assembly is not substantiallypinched), such that the infusion fluid can flow freely through thevalve. In some embodiments, the gravity flow position comprises a flowrate of at least about 600 ml/hr (e.g., 10-ml/min). In contrast, thecontrolled flow position (e.g., FIG. 10D) includes a pinch 808 in thetubing 606 b and movement of the pinch in the tubing (e.g., by thevalve), such that the rate of fluid flow (e.g., including flowdirection) is controlled by the valve. In some embodiments, thecontrolled flow position provides a flow rate of from about 0.001,0.002, 0.003, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008 or 0.009-ml/minor less to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09,0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1-ml/min or more. Insome embodiments, the controlled flow position provides a flow rate fromabout 0.006, 0.007, 0.008, 0.009, 0.01, or 0.02-ml/min to about 0.03,0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or 0.1-ml/min. In some embodiments,the controlled flow position provides a flow rate from about 0.5-ml/hrto 4-ml/hr. Accordingly, in preferred embodiments, the valve isconfigured and arranged to preclude tubing installation when the valveis in a controlled flow position. Preferably, the tubing is installedwhen the valve is in a gravity flow position (e.g., FIG. 10C), whereinthe valve is positioned such that the tubing can be installed in asubstantially straight (e.g., linear, un-pinched) configuration.

In preferred embodiments, the vascular access device (e.g., the catheterand/or fluid coupler) and the tubing 606 (e.g., tubing assembly 606 a)are configured and arranged to substantially preclude twisting (e.g.,rotational movement) between the vascular access device and the tubingwhen engaged (e.g., fluidly connected, in fluid communication with eachother). Accordingly, in some embodiments, the interconnecting portionsof the vascular access device and the tubing include a mechanicalstructure configured to prevent rotational movement of the connectionpast a predetermined point. For example, the interconnection of thevascular access device and the tubing includes a Leur lock, wherein thevascular access device includes the female portion of the Leurconnection and the tubing includes the male portion of the Leurconnection. In one embodiment, the female portion of the Leur connectorincludes a groove configured to mate with a detent on the male portionof the Leur connector, such that the male portion can be rotated withinthe female portion only until the detent enters the groove. In oneembodiment, additional mechanisms for prevent twisting between thevascular access device and the tubing are contemplated in the preferredembodiments.

Free Flow Mitigation

As described herein, the valve includes a gravity flow valve position,which allows fluid to flow freely through the valve and into the host.In preferred embodiments, the system is configured to regulate theamount of fluid allowed to flow into the host, since unregulated flow(e.g., free flow) of IV solution into the host could be deleterious tothe host's health. For example, if the IV solution contained a drug,such as insulin or heparin, infusion of too much IV solution could causean unsafe drop in blood sugar or an unsafe decrease in the host'sability to form blood clots, respectively. However, in certaincircumstances, such as a power failure, the system can be inadvertentlystopped in the gravity flow valve position. Accordingly, to preventunregulated flow (e.g., free flow) of fluid into the host, such as inthe event of a power failure and/or related circumstances, in preferredembodiments, the system includes a free flow mitigation device biased inan occluded position. In some embodiments, the system is configured andarranged such that the free-flow mitigation device precludes flowthrough the tubing responsive to power removal and/or loss of power tothe system and/or flow control device. In some embodiments, the freeflow mitigation device 606 e is incorporated into the tubing assembly606 a, such that flow through the tubing is blocked until the valveactivates (e.g., opens) the free flow mitigation device. In oneexemplary embodiment, the free flow mitigation device 606 e is aspring-clip occluder that closes (e.g., blocks, pinches, occludes) thetubing until it is activated. For example, in some embodiments, thevalve includes an electronic solenoid 807 that is configured andarranged to activate the spring-clip occluder (e.g., causes thespring-clip occluder to open, such that fluid can flow through thetubing, biases the free flow mitigation device in an un-occludedposition), when the tubing is installed in the valve. In preferredembodiments, the free flow mitigation device 606 e is located within thetubing 606 a such that the free flow mitigation device is aligned withthe portion of the valve that activates it. For example with referenceto FIG. 10A, the valve includes an electronic solenoid 807 located alonggrove 803, such that (when the tubing assembly is installed) thespring-clip occluder 606 e is aligned with the electronic solenoid. Inpreferred embodiments, the electronic solenoid is configured andarranged such that free flow mitigation device returns to the occludedposition (e.g., blocks free flow) responsive to power removal, such asduring a power failure, during installation of the tubing into the valve(e.g., at the beginning of a sensor session), turning the system off(e.g., at the end of use and/or of a sensor session), and the like.Preferably, the system is configured and arranged for electronic controlof the free flow mitigation device. For example, in preferredembodiments, the valve controls the flow of fluid into the host anddrawback of samples for testing, according to a flow profile (describedelsewhere herein). In preferred embodiments, the system is configured toelectronically control the opening and closing of the free flowmitigation device (e.g., by energizing and de-energizing the solenoid)in response to the flow profile. For example, when the flow profilespecifies infusion into the host or sample drawback, the systemelectronically activates the solenoid, which in turn biases the freeflow mitigation device in the open position, so that the fluid can beinfused, samples can be drawn back to the analyte sensor, samples can bereturned to the host, the analyte sensor can be washed with infusionsolution, drugs can be infused, and the like. Some free flow mitigationdevices suitable for use with the present system can be found in U.S.Pat. No. 5,810,323, U.S. Pat. No. 6,142,979, and U.S. Pat. No.6,749,591, all of which are incorporated by reference herein in theirentirety.

Sample-Contacting Sensor

In preferred embodiments, the integrated sensor system 600 is configuredsuch that at least the sensor's electroactive surfaces can be exposed toa sample and the sample's analyte concentration can be detected.Contacting the sensor 14 with the sample can be accomplished in avariety of ways, depending upon sensor and/or catheter configuration. Awide variety of catheter 12 and/or sensor 14 configurations can beimplemented in the preferred embodiments, to expose the sensor'selectroactive surfaces to a biological sample. In one exemplaryembodiment, the catheter 12 is disposed in the host's peripheralvascular system, such as in a peripheral vein or artery, and a bloodsample is taken up into the catheter 12 such that the blood contacts thesensor's electroactive surfaces. In another exemplary embodiment, thecatheter 12 can be disposed in the host's central vascular system or inan extracorporeal blood flow device, such as but not limited to anarterial-venous shunt, an extravascular blood-testing apparatus, adialysis machine and the like, wherein blood samples can be taken upinto the catheter 12 such that at least the sensor's electroactivesurfaces are contacted by the drawn up blood sample.

In one exemplary embodiment, the sensor 14 is configured to residewithin the catheter lumen 12 a (e.g., not protrude from the cathetertip); and the integrated sensor system 600 is configured to draw back asample into the catheter lumen 12 a such that at least the sensor'selectroactive surfaces are contacted by the sample. In some embodiments,the sensor 14 is a small-structured sensor having a width of less thanabout 1 mm. In one preferred embodiment, the sensor has a width of lessthan about 0.4 mm. In a more preferred embodiment, the sensor has awidth of less than about 0.2 mm. In some embodiments, the catheter 12has an internal diameter of from about 0.2 mm or less to about 2.0 mm ormore, preferably from about 0.5 mm to about 1.0 mm. In some embodiments,the sensor 14 is configured such that its electroactive surfaces are ator adjacent to its tip, and the flow control device 604 is configured totake up sample into the catheter lumen 12 a until the sample covers atleast the electroactive surfaces. In some embodiments, the electroactivesurfaces are distal from the sensor's tip and sample is drawn fartherback into the catheter lumen 12 a until the sample covers theelectroactive surfaces. In some embodiments, the tip of the sensor isdisposed about 3 cm, 2 cm, or 1 cm or less from a tip of the catheter.

In some embodiments, the sample taken up into the catheter's lumen 12 acovers only a portion of the sensor's in vivo portion. In otherembodiments, the sample taken up into the catheter's lumen 12 a coversthe entire in vivo portion of the sensor 14. In some embodiments, asample volume of from about 1 μl or less to about 2 ml or more is takenup into the catheter 12 and is sufficient to cover at least theelectroactive surfaces of the sensor 14. In some preferred embodiments,the sample volume is from about 10 μl to about 1 ml. In some preferredembodiments, the sample volume is from about 20 μl to about 500 μl. Inother preferred embodiments, the sample volume is from about 25 μl toabout 150 μl. In more preferred embodiments, the sample volume is fromabout 2 μl to about 15 μl.

In preferred embodiments, the sample taken up into the catheter's lumen12 a remains within the in vivo portion of the catheter 12. For example,in some embodiments, the sample is not drawn so far back into thecatheter 12 that it enters the ex vivo portion of the catheter 12, thetubing 606 or the reservoir 602. In some embodiments, however, thesample can be drawn back as far as the catheter but not into the IVtubing. In some embodiments wherein the catheter 12 is implanted in ahost, the blood sample never leaves the host's body (e.g., a planedefined by the host's skin). In some embodiments wherein the catheter 12is implanted in an extracorporeal device, the sample does notsubstantially exit the extracorporeal device. In preferred embodiments,wherein blood is taken up into the catheter 12, the blood is returned tothe host (or extracorporeal device), which is described elsewhereherein. In preferred embodiments, the sample is blood taken up from thehost's circulatory system and into the catheter 12 disposed within thecirculatory system.

In another exemplary embodiment of the integrated sensor system, thesensor is configured to protrude from the catheter's orifice 12 b, atleast intermittently. In preferred embodiments, the sensor is configuredto protrude sufficiently far out of the catheter's lumen 12 a (e.g.,into the circulatory system proper) that the sensor's electroactivesurfaces are contacted by sample (e.g., blood). In a further embodiment,the sensor is configured to intermittently protrude from the catheterorifice 12 b, such as by moving back and forth, such that theelectroactive surfaces are alternately disposed within the catheter 12and outside of the catheter 12. In one exemplary embodiment of acatheter is implanted in a host's vein, calibration solution 602 a isprovided within the catheter 12 such that the sensor 14 is disposedwithin the catheter 12, the sensor 14 is contacted by the calibrationsolution 602 a and calibration measurements can be obtainedperiodically, when the sensor 14 (e.g., electroactive surfaces) is movedoutside of the catheter 12, the sensor 14 is contacted by blood andblood analyte measurements can be obtained.

In some embodiments of the integrated sensor system 600, the catheter 12and sensor 14 are configured to take advantage of flow dynamics withinthe host's vascular system. By taking advantage of flow dynamics, thesystem can be simplified, such that the flow control device functionsmainly to allow or block the flow of calibration solution.

FIG. 9 is a cut-away illustration of one exemplary embodiment, in whicha catheter 12 is implanted in a host's vessel 906, such as but notlimited to an artery or vein. The catheter 12 includes a sidewall 904that can be configured to include one or more holes 902 (e.g., orificesor openings configured for fluid passage, such as from the exteriorsidewall surface into the catheter lumen 12 a). The catheter 12 can beinserted into the host's vein (or artery, or an extracorporealcirculatory device) such that the catheter points either in thedirection of blood flow (antegrade) or against the direction of bloodflow (retrograde). The catheter is configured such that in an antegradeposition, blood flows into the catheter lumen 12 a via the holes 902 andthen out of the catheter orifice 12 b. In a retrograde position, bloodenters the catheter lumen 12 a via the catheter orifice 12 b and flowsout of the lumen through the holes 902. In some embodiments, the sensor14 can be disposed within the catheter lumen 12 a such that bloodflowing between the holes 902 and the orifice 12 b contacts at least thesensor's electroactive surfaces. In some embodiments, the sensor 14 isconfigured to be substantially immobile within the lumen 12 a, while inother embodiments the sensor 14 is configured to be substantiallymoveable within the lumen 12 a, as described in more detail elsewhereherein.

Generally, the holes 902 can be placed in any location on the catheter'ssidewall 904. In some embodiments, the holes 902 can be located near oradjacent to the catheter orifice 12 a. In other embodiments, the holes902 can be placed remotely from the catheter orifice 12 a. The size,shape and number of holes 902 can be selected to optimize the samplevolume and flow rate through the catheter lumen 12 a. For example, insome embodiments, the holes 902 are round, ellipsoid, rectangular,triangular, star-shaped, X-shaped, slits, combinations thereof,variations there of, and the like. Similarly, in some embodiments, thecatheter 12 can have from 1 to about 50 or more holes 902. In otherembodiments, the catheter can have from 2 to about 10 or more holes 902.

In some alternative embodiments, the catheter includes at least one sizewall orifice in place of an end tip orifice, which allows selectiveexposure of the sensor to the host's biological sample there through. Avariety of alternative catheter configurations are contemplated inconjunction with the preferred embodiments.

In one exemplary embodiment of the integrated sensor system 600, theflow control device 604 is configured to intermittently block theinfusion of solution 602 a through the catheter 12, which is configuredwith side holes 902 as described above. Additionally, the analyte sensoris disposed within the catheter lumen 12 a such that sample passingbetween the side holes 902 and the catheter orifice 12 b bathes thesensor's electroactive surfaces, during which time an analytemeasurement can be obtained. When the flow control device 604 does notblock infusion, the solution 602 a contacts the sensor's electroactivesurfaces; and calibration measurements can be taken.

In some embodiments, a solution 602 a can be infused into the catheter12 at a rate such that the flow of sample between the holes 902 and theorifice 12 b is substantially blocked and at least the electroactivesurfaces are bathed in the solution 602 a (e.g., undiluted solution). Inpreferred embodiments, the sensor 14 can be calibrated while it isbathed in the undiluted solution 602 a.

In preferred embodiments, the sensor 14 is a small-structured sensorwith at least one electrode, such as a working electrode, as describedelsewhere herein. In some embodiments, the sensor 14 has two or moreelectrodes, such as but not limited to working, reference and counterelectrodes. In some embodiments, the sensor 14 includes a referenceelectrode disposed remotely from the working electrode, as discussedelsewhere herein. In some embodiments, the sensor 14 includes two ormore electrodes that are separated by an insulator, such as described inU.S. Patent Publication No. US-2007-0027385-A1, herein incorporated byreference in its entirety. In preferred embodiments, the electrode is afine wire, such as but not limited to a wire formed from platinum,iridium, platinum-iridium, palladium, gold, silver, silver chloride,carbon, graphite, gold, conductive polymers, alloys and the like. Insome exemplary embodiments, the sensor 14 includes one or moreelectrodes formed from a fine wire with a diameter of from about 0.001or less to about 0.010 inches or more. Although the electrodes can byformed by a variety of manufacturing techniques (bulk metal processing,deposition of metal onto a substrate, and the like), it can beadvantageous to form the electrodes from plated wire (e.g., platinum onsteel wire) or bulk metal (e.g., platinum wire). It is believed thatelectrodes formed from bulk metal wire provide superior performance(e.g. in contrast to deposited electrodes), including increasedstability of assay, simplified manufacturability, resistance tocontamination (e.g. which can be introduced in deposition processes),and improved surface reaction (e.g. due to purity of material) withoutpeeling or delamination.

In some embodiments, one or more electrodes are disposed on a support,such as but not limited to a planar support of glass, polyimide,polyester and the like. In some exemplary embodiments, the electrodesinclude conductive inks and/or pastes including gold, platinum,palladium, chromium, copper, aluminum, pyrolitic carbon, compositematerial (e.g., metal-polymer blend), nickel, zinc, titanium, or analloy, such as cobalt-nickel-chromium, or titanium-aluminum-vanadium,and are applied to the support using known techniques, such as but notlimited to screen-printing and plating. Additional description can befound in U.S. Pat. No. 7,153,265, U.S. Patent Publication No.US-2006-0293576-A1, U.S. Patent Publication No. US-2006-0253085-A1, U.S.Pat. No. 7,003,340, and U.S. Pat. No. 6,261,440, each of which isincorporated in its entirety by reference herein.

In some embodiments, an optional redundant sensor can be disposed withinthe catheter lumen, in addition to the sensor 14 described elsewhereherein. In one exemplary embodiment, a sensor 14 and a redundant sensorare disposed within the lumen of a sensor implanted in a host'speripheral vein, such that the electroactive surfaces of the sensor 14are more proximal to the catheter orifice 12 b than the electroactivesurfaces of the redundant sensor; wherein blood is taken up into thelumen 12 a such that the electroactive surfaces of both the sensor 14and the redundant sensor are contact by the blood; such that analyte canbe detected by both the sensor 14 and the redundant sensor and theredundant sensor measurements are used by the system 600 to confirm thesensor's 14 measurements. In a further embodiment, both the sensor 14and the redundant sensor are intermittently concurrently contacted bythe solution 602 a such that both the sensor 14 and the redundant sensorcan take calibration measurements of the solution 602 a, wherein thecalibration measurements of the redundant sensor are at least used toconfirm the calibration measurements of the sensor 14. In anotherembodiment, the calibration measurements from both the sensor 14 and theredundant sensor are used to calibrate the sensor 14.

Local Analyzer

Referring to FIGS. 6 and 7, in some embodiments, the integrated sensorsystem 600 includes a local analyzer 608 configured to operably connectto a remote analyzer 610. In some embodiments, the local analyzer 608 isproximal to an analyte sensor 14 and the remote analyzer 610 isconfigured to operably connect to the local analyzer. However,alternative configurations are possible, such as the analyte sensor 14can be operably connected to both the local and remote analyzers 608,610 respectively. The remote analyzer 610 of the preferred embodimentsis discussed below. In various embodiments, one or more functions of thelocal analyzer 608 can be transferred to the remote analyzer, as isappreciated by one skilled in the art. Likewise, in some embodiments,one or more functions of the remote analyzer 610 can be incorporatedinto the local analyzer 608. In further embodiments, functions of thelocal and/or remote analyzers 608, 610 can be disposed in one, two,three or more physical bodies (e.g., separate housings), depending uponthe integrated sensor system 600 configuration and/or componentcombinations. For example, in one embodiment, the local analyzer 608includes a potentiostat, a power source (e.g., battery or connection toan electrical source), and data storage; and the local analyzer 608 isconfigured such that the potentiostat is disposed on the sensor's fluidcoupler 20 and the remaining local analyzer 608 components are disposedelsewhere between the local analyzer 608 and the remote analyzer 610(e.g., connected by wiring).

Operable connections between the local and remote analyzers 608, 610 andthe analyte sensor 14 can be accomplished by a hard wire (e.g., USB,serial), RF communication, IR communication, and the like. In someembodiments, operable connections include a connector known in the art,such as but not limited to mating plug and socket units, screwconnectors, clips and the like. In some embodiments, the connectors areseparable. In other embodiments, the connectors are inseparable. In someembodiments, the connectors include a lock, to prevent inadvertentdisconnection. In some embodiments, the local analyzer can be isolatedfrom the remote analyzer by an isolation transformer.

In some embodiments, the local analyzer 608 is operably connected to thesensor 14 (e.g., the sensor electrode(s)), such as by a wire connection.A detailed description of electronic components and configurations isdescribed elsewhere herein, for example, in the section entitled “SensorElectronics.” In some embodiments, the local analyzer 608 is disposed onor adjacent to the sensor, such as on the sensor fluid coupler 20. Inone exemplary embodiment, the sensor's fluid coupler 20 includes a localanalyzer housing that includes at least a potentiostat. In someembodiments, the housing can include a battery and electronics, suchthat the sensor 14 can be powered, and data can be collected and/ortransmitted to additional system electronics (e.g., electronics unitsdisposed remotely from the sensor, such as on the host's arm, on thehost's bed and in the remote analyzer, and the like). In someembodiments, the local analyzer 608 includes a small housing that isconnected to the sensor 14 via a short wire (e.g., from about 1 cm orless to about 10 cm or more) and is taped to the host's skin, such asadjacent to the catheter's insertion site on the host's arm or hand. Ina further embodiment, the local analyzer 608 includes a connector, suchas but not limited to a “plug” configured to mate with a “socket” wiredto the sensor 14, such that an electrical connection can be made betweenthe local analyzer 608 and the sensor 14. In another embodiment, thesensor 14 includes a cable having a plug configured to connection to thelocal analyzer 608 via a socket. In still another embodiment, both thesensor 14 and the local analyzer 608 include cables configured to matewith each other via a plug and socket mechanism. Advantageously, adetachable configuration allows catheter/sensor insertion without acumbersome connection to the local analyzer 608 as well as re-use of thelocal analyzer 608. In an alternative exemplary embodiment, the localanalyzer 608 is permanently connected to the sensor 14 and cannot bedisconnected therefrom; a single use, permanently connectedconfiguration can simplify application to the host, can reduce thepossibility of cross-contamination between hosts, does not requirecleaning and/or sterilization between hosts, and can reduce operatorerror during application to the host.

In preferred embodiments, the local analyzer 608 includes at least theminimal electronic components and/or programming required to energizethe sensor 14 and collect data therefrom, such as but not limited to apotentiostat. However, in some embodiments, the local analyzer 608includes additional electronic components that can be programmed toanalyze one or more components of the collected raw signal, or to storedata, calibration information, a patient ID and the like. In oneexemplary embodiment, the local analyzer 608 includes a potentiostat anda battery back up. The battery back up can maintain a potential on thesensor and store data (calibration and/or collected host data) for briefperiods of time when the electronics can be disconnected, such as whenthe host is moved from one location to another. In one exemplaryembodiment, the local analyzer 608 is disposed on or adjacent to thesensor 14 and is configured such that the host can be connected to afirst remote analyzer 610 at one station, and then disconnected from thefirst remote analyzer 610, moved to a new location and connected to asecond remote analyzer 610 at the new location, and the local analyzer608 retains sufficient data that the system 600 functions substantiallywithout initialization or substantial delay upon connection to the new(second) remote analyzer 610. In another example, the host can bedisconnected from the first remote analyzer 610, taken to anotherlocation for a procedure (e.g., for surgery, imaging, and the like) andthen reconnected to the first remote analyzer 610 upon return to theoriginal location without substantial loss of system 600 function uponreconnection.

In some embodiments, the local analyzer 608 includes two or more parts,such that only the potentiostat is disposed on or adjacent to the sensor14 (e.g., sensor fluid coupler 20) or the catheter (e.g., catheterconnector 18); other portions of the local analyzer 608 can be disposedremotely from the host, such as in a separate housing wired to thesensor and to the remote analyzer. In one exemplary embodiment, the twoparts of the local analyzer 608 can be separated (e.g., unplugged) suchthat the host can be moved and the local analyzer 608 portion that isattached to the host goes with the host while the remaining portionstays with the remote analyzer 610.

In still other embodiments, all sensor electronics components aredisposed remotely from the host, such as in the remote analyzer 610. Forexample, the sensor 14 can include an appropriate connector, plug and/orwiring to connect the sensor 14 to the remote analyzer 610, which powersthe sensor 14, collects raw data from the sensor 14, calibrates thesensor 14, analyzes and presents the data, and the like. In one example,the sensor 14 includes a cable of sufficient length to permit pluggingthe sensor 14 into a remote analyzer 610 disposed at the host's bedside.

In still other embodiments, the local analyzer 608 can be incorporatedinto the remote analyzer 610, such as housed in the same body as theremote analyzer 610, for example. In one exemplary embodiment, both thelocal and remote analyzers 608, 610 are disposed in a housing attachedto a support 612 (e.g., connected to an IV pole, placed on a bedsidetable, connected to the wall, clamped to the head of the host's bed) andconnected to the analyte sensor via a wire or cable. In someembodiments, the cables/wires (e.g., for connecting the sensor to thelocal analyzer and/or the remote analyzer, and/or connecting the localanalyzer to the remote analyzer) can be provided in the IV tubing set.

Remote Analyzer

As discussed in the section entitled “Local Analyzer,” the integratedsensor system 600 includes a remote analyzer 610. In preferredembodiment, the remote analyzer 610 is configured to at leastcommunicate with the local analyzer 608 and can be configured to controlthe flow control device 604 described in the sections entitled “FlowControl Device,” and “Flow Control Device Function.” Generally, theremote analyzer 610 is powered from a standard 120 VAC wall circuit orother suitable power source, for example. In some embodiments, theremote analyzer 610 is disposed at the host's bedside and can beconfigured to be disposed on a support 612, such as but not limited to,mounted a mobile IV drip pole, attached to the wall, clamped to thehost's bed, or sitting on a table or other nearby structure.

In preferred embodiments, the remote analyzer 610 includes a display,such as but not limited to a printout, an LED display, a monitor, atouch-screen monitor and the like. In some embodiments, the remoteanalyzer 610 includes both a hard copy display, such as a printerconfigured to print collected data, and a monitor. In some embodiments,the remote analyzer 610 is a programmable touch-screen panel PCconfigured to have different “screens” and “buttons” for control ofsystem components (e.g., the sensor 14, the flow control device 604,etc.) and to display data, such as but not limited to hostidentification and condition, host food intake, medication schedules anddosage information, sensor identification, raw data, processed data,calibration information, and the like, such as in tables and/or graphs.In further preferred embodiments, the remote analyzer 610 is configuredto be programmed, such that the operator can initiate system functionssuch as IV fluid line priming, starting and/or stopping the flow controldevice 604, select among two or more solutions (e.g., between glucoseconcentrations), select the mode of data delivery (e.g., printer oron-screen), send data to a central location (e.g., the nurse's stationor medical records), set alarms (e.g., for low and high glucose), andthe like.

In some embodiments, the system 600 is configured to integrate with(e.g., be used in conjunction with) third party medical devices, such asbut not limited to a pulse-oxygen meter, a blood pressure meter, a bloodchemistry machine, and the like. In such embodiments, the local and/orremote analyzers 608, 610 can be configured to communicate with thethird party medical devices, such as but not limited to a patientmonitor.

Flow Control Device Function

In some embodiments, the remote analyzer 610 controls the function ofthe flow control device 604. In some embodiments, the flow controldevice includes electronics configured to control the flow controldevice. The flow control device 604 can be configured to perform anumber of steps of operation, which are discussed below. Depending uponthe system configuration and physician preferences, in some embodiments,one or more of the steps can be performed. In some embodiments, all ofthe steps are performed. In some embodiments, the steps of operation canbe performed in the order in which they are presented herein. In otherembodiments, the order of steps of operation can be varied (e.g.,repeated, omitted, rearranged), depending upon various parameters, suchas but not limited to the calibration solution 602 a selected, theparticular infusion set selected, catheter 12 size, host condition,analyte of interest, type of sample and location of sample collection,integration with third party devices, additional infusion of fluids andthe like.

FIGS. 8A through 8C are schematic illustrations of a flow control devicein one exemplary embodiment, including its relative movement/positionsand the consequential effect on the flow of fluids through thesensor/catheter inserted in a host. In general, steps performed by theflow control device 604, include the steps of: contacting the sensor 14with calibration solution 602 a (including sensor calibration) andcontacting the sensor with a biological sample to be measured. In someembodiments, additional steps can be taken, such as but not limited tokeep a vein open (KVO) step and a wash step. In the exemplary embodimentpresented in FIGS. 8A though 8C, the flow control device 604 is a rollervalve configured to move between at least two positions, 810 and 812,respectively. Movement of the flow control device 604 between positions810 and 812 effectively concurrently moves the pinch point 808 (e.g.,the point at which tubing 606 is pinched) between positions 810 and 812.Additional flow control device positions are discussed below.

The top of FIGS. 8A through 8C are schematic drawings illustratingpositions of the flow control device 604. The bottom of FIGS. 8A through8C, are a cut-away views of an implanted catheter 12, including anindwelling sensor 14, illustrating the corresponding activity at theimplantation site, in response to movements of the flow control device604. For simplicity, for purposes of discussion only, it is assumed thatthe catheter 12 is implanted in a host's vein, that the sensor 12 doesnot protrude from the catheter's orifice 12 b and that the catheter 14does not include side holes 902. However, one skilled in the artappreciates that the catheter 14 could be implanted into any vessel ofthe host or into a variety of extracorporeal devices discussed elsewhereherein.

Step One: Contacting Sensor with Calibration Solution

In general, the system is configured to allow a calibration solution tocontact the sensor using a flow control device such as a pump, valve orthe like. In some embodiments, such as shown in FIGS. 8A through 8C, theflow control device 604 is a valve configured with a first structure 802and a second structure 806. For convenience, the first structure 802 isdepicted as a roller connected to a rotatable axle 804, however any flowcontrol device such as described in the section entitled “Flow ControlDevice,” can be configured to utilize the concepts and/or functionsdescribed herein. In general, when the flow control device is a valve,the valve is configured to allow no flow, gravity flow and/or meteredflow through movement of the valve between one or more discreetpositions.

In the embodiment shown in FIGS. 8A through 8C, the flow control device604 is configured such that a tube 606 threaded between the first andsecond structures 802, 806 (e.g., between the roller and the surfaceagainst which the roller presses) is compressed substantially closed.For convenience, the compressed location on the tubing is referred toherein as the “pinch point” 808. In some embodiments, the flow controldevice 604 is configured such that the pinch point is moved along thetubing, either closer to or farther from the host. As the pinch point808 is moved closer to the host, the tube 606 is progressivelycompressed, causing fluid (e.g., solution 602) to be pushed into thehost's vascular system (see the corresponding illustration of the sensorwithin the host's vessel at the bottom of FIG. 8A), at the catheter 12implantation site. Conversely, as the pinch point 808 is moved away fromthe host, the portion of tubing 606 on the host side of the pinch point808 progressively expands, causing sample (e.g., blood) to be drawn upinto the catheter lumen 12 a. In an alternative embodiment, the flowcontrol device 604 is configured such that the pinch point issubstantially stationary and the first and second structures selectivelycompress the tubing at the pinch point (e.g., the tube 606 is eitherpinched fully closed or is fully open), which either stops or allows theflow of solution 602 a.

In the exemplary embodiment shown in FIG. 8A (bottom), the catheter 12is implanted in the host's vein 906 (or artery), as described elsewhereherein. A sensor 14 is disposed with the catheter 12. The catheter 12 isfluidly connected to a first end of tubing 606 that delivers thesolution 602 a to the catheter 12. The solution 602 a can move out ofthe catheter 12 and a sample of blood 814 can move in and out of thecatheter 12, via the catheter's orifice 12 b. In some alternativeembodiments, the catheter 12 includes optional sidewall holes 902 (seeFIG. 9, described elsewhere herein) and the solution 602 a and blood canmove in and out of the catheter 12 via the sidewall holes 902 and thecatheter orifice 12 b. In some alternative embodiments, the sensor isconfigured to move in and out of the catheter. In some embodiments, thecatheter orifice 12 b is disposed in the sidewall 904 (e.g., near thecatheter's tip) instead of at the tip. Tubing 606 is fluidly connectedto the reservoir 602 on a second end (see FIGS. 6 and 7).

Referring now to a calibration phase to be performed by the exemplaryvalve of FIG. 8A, in preferred embodiments, the flow control device 604is configured to perform a step of contacting the sensor 14 withsolution 602 a, wherein the flow control device 604 moves from position810 to position 812 (e.g., forward, toward the host/catheter). When theflow control device 604 moves from position 810 to position 812, thepinch point 808 is moved from position 810 to position 812. As the pinchpoint 808 is moved from position 810 to position 812, a first volume ofthe calibration solution 602 a is pushed through the tubing 606, towardthe catheter 12.

Referring again to the bottom of FIG. 8A, a second volume of thesolution 602 a, which is substantially equal to the first volume, ispushed into the host's vein 906, in response to the first volume ofsolution 602 a moving toward the host. As the second volume of solution602 a is pushed through the catheter 12 and into the host's vein thesecond volume contacts (e.g., bathes) the analyte sensor 14, includingthe analyte sensor's electroactive surfaces. In some embodiments, thevolume (e.g., the first and second volumes of fluid) moved is from about3 μl or less to about 1 ml or more. In some preferred embodiments, thevolume is from about 10 μl to about 500 μl, or more preferably fromabout 15 μl to about 50 μl. In general, the volume of fluid pushedthrough the catheter in a particular phase (e.g., calibration phase) isdependent upon the timing of the phase. For example, if a long phase,such as a 20 minute calibration phase (e.g., as compared to a shorter 5minute phase) were selected, the volume of fluid pushed during the longphase would be 4× greater than the volume of fluid pushed during theshorter phase. Accordingly, one skilled in the art appreciates that theabove described ranges of fluids infusion can be increased and/ordecreased simply be increasing or decreasing the measurement phaseand/or intervals (i.e., timing). In preferred embodiments, the fluid ismoved at a flow rate that is sufficiently slow that the calibrationsolution's temperature substantially equilibrates with the temperatureof the tissue surrounding the in vivo portion of the catheter and/ortemperature of bodily fluid (e.g., blood), such that the temperature ofthe calibration solution and the temperature of the blood aresubstantially the same. In preferred embodiments, the flow rate is fromabout 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4,0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, 0.01, 0.001 μl/min or less toabout 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9,9.5, 10.0 ml/min or more. In one exemplary embodiment, the flow controldevice 604 maintains a flow rate from about 0.9, 0.8, 0.7, 0.6, 0.5,0.4, 0.3, 0.2, 0.1 or 0.05 μl/min or less to about 1.0, 1.1, 1.2, 1.3,1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 ml/min or more. In one exemplaryembodiment, the flow rate is from about 1 μl/min to about 1.0 ml/min. Inone exemplary embodiment, the flow rate is from about 0.01 ml/min toabout 0.2 ml/min. In another exemplary embodiment, the flow rate is fromabout 0.05 ml/min to about 0.1 ml/min. In some embodiments, the flowrate is 0.0 ml/min.

In some embodiments, the system is configured such that the speed of themovement between the first and second discreet positions is regulated ormetered to control the flow rate of the fluid through the catheter. Insome embodiments, the system is configured such that the time ofmovement between the first and second discreet positions is from about0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1,0.15, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 seconds orless to about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8,8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29 or 30 seconds or more, preferably from about 0.5 to10 seconds. In some embodiments, the system is configured such that anamount of pinch of the tubing regulates the flow rate of the fluidthrough the catheter. In some embodiments, the fluid flow is regulatedthrough a combination of metering and/or pinching techniques, forexample. Depending on the type of flow control device (e.g., valve), avariety of methods of metering and/or regulating the flow rate can beimplemented as is appreciated by one skilled in the art.

Preferably, the sensor is configured to measure a signal associated withthe solution (e.g., analyte concentration) during the movement of theflow control device from position 810 to position 812 and/or duringcontact of the sensor 14 with the solution 602 a. Electronics, such asan electronic module included in either the local or remote analyzer608, 610 controls signal measurement and processing, such as describedin more detail elsewhere herein.

In general, a calibration measurement can be taken at any time duringthe flow control device 604 movement from position 810 to position 812,and including a stationary (stagnant) time there after. In someembodiments, one or more calibration measurements are taken at thebeginning of the flow control device 604 movement from position 810 toposition 812. In other embodiments, one or more calibration measurementsare taken at some time in the middle of the flow control device 604movement from position 810 to position 812. In some embodiments, one ormore calibration measurements are taken near the completion of the flowcontrol device 604 movement from position 810 to position 812. In someembodiments, one or more calibration measurements are taken aftercompletion of the flow control device 604 movement from position 810 toposition 812. In still other embodiments, the flow control device ispositioned such that fluid can flow followed by positioning the flowcontrol device such that there is no fluid flow (e.g., 0 ml/min) duringthe calibration measurement. In preferred embodiments, one or morecalibration measurements are taken when the temperature of the solution602 a has substantially equilibrated with the temperature of the tissuesurrounding the in vivo portion of the implanted catheter 12. Processingof calibration measurements and sensor calibration are describedelsewhere herein.

As a non-limiting example, in some embodiments, the sensor can becalibrated using one or more reference solutions. For example, if theanalyte is glucose, a suitable reference (e.g., calibration solution) issaline containing 0, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275,300 mg/dl glucose or more. In some embodiments, two or more suchreference solutions can be used to calibrate the sensor. In someembodiments, a baseline value of the sensor can be obtained bygenerating a signal when the sensor is exposed to a 0 mg/dl referencesolution (e.g., 0 mg/dl analyte). In some embodiments, updated baselinevalues are continuously obtained by repeatedly exposing the sensor tothe 0 mg/dl reference solution, such as every 1, 2, 3, 4, 5, 10, 20, 30,40, 50, or 60 or more minutes. In some embodiments, updated baselinevalues are continuously obtained by exposing the sensor to the 0 mg/dlreference solution for periods of time and continuously collectingbaseline values. For example, the sensor can be exposed to the 0 mg/dlreference solution for 5, 10, 15, 20, 25, 30, 40, 50, or 60 minutes, orlonger, while baseline signals are continuously generated. In thisembodiment, sensitivity m calibration values can be obtainedintermittently by exposing the sensor to an analyte-containing referencesolution intermittently, such as but not limited to every 5, 10, 15, 20,25, 30, 40, 50, or 60 minutes, or longer, such as at the conclusion ofthe exposure to the 0 mg/dl solution. In other embodiments, suchcalibrations measurements (e.g., to obtain a baseline value) areperformed “intermittently,” such as once every 24 hours.

In some embodiments, sensitivity m calibration values are obtainedsubstantially continuously/continually, such as by exposure of thesensor to one or more analyte-containing reference solutions every 1, 2,3, 4, 5, 10, 20, 30, 40, 60 or more minutes. In some embodiments,sensitivity m calibration values are obtained substantiallycontinuously/continually by exposure of the sensor to one or moreanalyte-containing reference solutions for a period of time, such as butnot limited to for 5, 10, 15, 20, 25, 30, 40, 50, or 60 minutes, orlonger, while sensitivity signals are continuously generated. In oneexemplary embodiment, continuous calibration measurements are performedby passing a 100-mg/dl glucose calibration solution across the sensor(e.g., to detect shifts in sensitivity m), and the intermittentcalibration measurements are performed to determine baseline b, bypassing a 0-mg/dl calibration solution across the sensor. While notwishing to be bound by theory, it is believed that in somecircumstances, baseline drift is greater than sensitivity drift.Accordingly, in some embodiments, the system is configured to performbaseline calibration measurements (with 0-mg/dl glucose) automatically(e.g., every 5-minutes) and a sensitivity calibration measurement (with100-mg/dl) intermittently (e.g., every hour).

Step Two: Sample Collection and Measurement

In general, the system is configured to allow a sample (e.g., blood) tocontact the sensor using the flow control device. Referring now to thetop of FIG. 8B, the flow control device 604 is configured to draw back(or take-in) a sample (e.g., blood) from the host. For example, tocollect a sample, the flow control device 604 reverses and movesbackward (e.g., away from the host/catheter), from position 812 toposition 810, thereby causing the pinch point 808 to move away from thehost. As the pinch point is moved from position 812 to position 810, thetube 606 (on the host side of the pinch point 808) expands (e.g., thetube volume increases).

Referring now to the bottom of FIG. 8B, as the tube volume increases, asmall, temporary vacuum is created, causing sample 814 (e.g., blood) tobe taken up into the catheter lumen 12 a. In some embodiments, the flowcontrol device 604 is configured to take up a sufficient volume ofsample 814 such that at least the sensor's electroactive surfaces arecontacted by the sample 814. In some embodiments, a sample volume offrom about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25,20, 15, 10, 9.0, 8.0, 7.0, 6.0, 5.0, 4.0, 3.0, 2.0, 1.0, 0.9, 0.8, 0.7,0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 μl or less to about 0.1, 0.15, 0.2,0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85,0.9, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 ml ormore is taken up into the catheter 12 and is sufficient to cover atleast the electroactive surfaces of the sensor 14. In some embodiments,the sample volume is from about 10 μl to about 1 ml. In someembodiments, the sample volume is from about 20 μl to about 500 μl. Inother embodiments, the sample volume is from about 25 μl to about 150μl. In other embodiments, the sample volume is from about 2 μl to about15 μl.

In some embodiments, the sample taken up into the catheter is taken upsubstantially no farther than the skin (or a plane defined by the skinof the patient). In some embodiments, the sample is taken up into thecatheter substantially no farther than the catheter's inner lumen (e.g.,substantially not into the IV tubing.)

In some embodiments, the rate of sample take-up is sufficiently slowthat the temperature of the sample substantially equilibrates with thetemperature of the surrounding tissue. Additionally, in someembodiments, the rate of sample take-up is sufficiently slow such thatsubstantially no mixing of the sample 814 and solution 602 a occurs. Insome embodiments, the flow rate is from about 0.9, 0.8, 0.7, 0.6, 0.5,0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02,0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002 or 0.001ml/min or less to about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9or 2.0 ml/min or more. In one exemplary embodiment, the flow rate isfrom about 0.001 ml/min or less to about 2.0 ml/min or more. Inpreferred embodiments, the flow rate is from about 0.01 ml/min to about1.0 ml/min. In one exemplary preferred embodiment, the flow rate is fromabout 0.02 ml/min to about 0.35 ml/min. In another exemplary preferredembodiment, the flow rate is from about 0.0.02 ml/min to about 0.2ml/min. In yet another exemplary preferred embodiment, the flow rate isfrom about 0.085 ml/min to about 0.2 ml/min.

As described above, in some embodiments, the system is configured suchthat the speed of the movement between the first and second discreetpositions is regulated or metered to control the flow rate of the fluidthrough the catheter. In some embodiments, the system is configured suchthat the time of movement between the first and second discreetpositions is from about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05,0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9 or 1.0 seconds to about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6,6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 seconds, preferably from about0.5 to 10 seconds. In some embodiments, the system is configured suchthat an amount of pinch of the tubing regulates the flow rate of thefluid through the catheter. In some embodiments, regulate the fluid flowthrough a combination of metering and/or pinching techniques, forexample. Depending on the type of flow control device (e.g., valve), avariety of methods of metering and/or regulating the flow rate can beimplemented as is appreciated by one skilled in the art.

Measurements of sample analyte concentration can be taken while theelectroactive surfaces are in contact with the sample 814. Anelectronics module included in the local and/or remote analyzer 608, 610controls sample analyte measurement, as described elsewhere herein. Insome embodiments, one sample measurement is taken. In some embodiments,a plurality of sample measurements are taken, such as from about 2, 3,4, 5, 6, 7, 8, 9, or 10 measurements to about 20, 25, 30, 35, 40, 45 or50 or more measurements and/or at a sample rate of from about 1measurement per second to about 1 measurement per minute. In someembodiments, the rate is from about 1 measurement per 2 seconds to about1 measurement per 30 seconds. In preferred embodiments, samplemeasurements are taken substantially continuously, such as but notlimited to substantially intermittently, as described elsewhere herein.

Optional Step: Flush

In some exemplary embodiments, the flow control device 604 is configuredto perform one or more steps, in addition to steps one and two,described above. A flush step, during which the sensor 14 and/orcatheter 12 are substantially washed and/or cleaned of host sample, isone such optional step.

Referring now to the top of FIG. 8C, the exemplary flow control device604 performs a flush step by moving forward from position 810 (e.g.,toward the host/catheter), past position 812 (e.g., around and over thetop of structure 804) and back to position 810. For convenience, themovement illustrated by an arrow in the top of FIG. 8C is referred toherein as the “flush movement.”

Referring now to the bottom of FIG. 8C, the flush movement pushesforward a volume of solution 602 a (e.g., a third volume) that pushesthe collected blood sample 814 into the host. In some embodiments, thethird volume of solution 602 a is substantially equal to the first andsecond volumes described above. In some embodiments, the flush movementis repeated at least one time. In some embodiments, the flush movementis repeated two, three or more times. With the exception of the firstflush movement, which pushes the sample 814 back into the host, eachrepeat of the flush movement pushes a volume of solution 602 a into thehost, for example. In some embodiments, the flush movement pushes thethird volume of solution 602 a into the host at a rate of from about0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06,0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004,0.003, 0.002 or 0.001 ml/min or less to about 1.0, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0,6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 ml/min or more. In someembodiments the flush movement pushes the third volume of solution intothe host at a rate of from about 1.0 μl/min to about 1.0 ml/min. Inalternative embodiments, the flow control device 604 is moved to a fullyopened position (e.g., no pinch) and the flow regulator 602 b is set ata setting that allows more solution (e.g., an increased volume and/or ata faster rate) to infuse into the host than during the calibration phase(e.g., step one, above). In preferred embodiments, the flush movementwashes enough blood off of the analyte sensor's electroactive surfacesthat the sensor 14 can measure the solution 602 a substantially withoutany interference by any remaining blood. In some embodiments, the flushstep is incorporated into step one, above.

Generally, the solution 602 a is flushed through the catheter 12, toensure that a sufficient amount of the sample has been removed from thesensor 14 and the catheter lumen 12 a, such that a calibrationmeasurement can be taken. However, in some embodiments, sample iscollected, measured and flushed out, followed by collection of the nextsample, substantially without sensor calibration; the flush step can beexecuted between samples to ensure that the sample being analyzed issubstantially uncontaminated by the previous sample. In someembodiments, a relatively extended flush is used, while in otherembodiments the flush is just long enough to ensure no blood remains.

In some embodiments, the effectiveness of the flushing movement isdependent upon the solution 602 a composition (e.g., concentrations ofsodium chloride, glucose/dextrose, anticoagulant, etc.). Accordingly,the amount of solution 602 a required to ensure that substantially nosample remains in the catheter 12 and/or on the sensor 14 can depend onthe solution 602 a composition. For example, relatively more flushmovements may be required to completely remove all of the sample when anon-heparinized solution is selected than when a heparinized solution isselected. In some embodiments, the effectiveness of the flushingmovement is also dependent upon the flush flow rate. For example, arelatively faster flow rate can be more effective in removing samplefrom the sensor than a slower flow rate, while a slower flow rate canmore effectively move a larger volume of fluid. Accordingly, in someembodiments, the number of flush movements selected is dependent uponthe calibration solution and flow rate selected. In some embodiments,the flush step flow rate is from about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4,0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01,0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002 or 0.001 ml/minor less to about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0,2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0,9.5, or 10.0 ml/min or more, and last for from about 55, 50, 45, 40, 35,30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 seconds or less toabout 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3,2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3 minutes or more. In one exemplaryembodiment, about 0.33 ml of solution 602 a is flushed at a rate ofabout 1.0 ml/min, which takes about 20 seconds.

In some embodiments, the flush step returns the sample 814 (e.g., blood)to the host, such that the host experiences substantially no net sampleloss. Further more, the flush movement washes the sensor 14 and catheterlumen 12 a of a sufficient amount of sample, such that an accuratecalibration measurement (e.g., of undiluted solution 602 a) can be takenduring the next step of integrated sensor system 600 operations. In someembodiments, the number of sequential flush movements is sufficient toonly wash substantially the sample from the sensor 14 and catheter lumen12 a. In other embodiments, the number of sequential flush movements canbe extended past the number of flush movements required to remove thesample from the sensor and catheter lumen, such as to provide additionalfluid to the host, for example.

At the completion of the flush step, the flow control device 604 returnsto step one, illustrated in FIG. 8A. In some embodiments, the stepsillustrated in FIGS. 8A through 8C are repeated, until the system 600 isdisconnected from the catheter/sensor, either temporarily (e.g., to movea host to an alternate location for a procedure) or permanently (e.g.,at patient discharge or expiration of sensor life time). In someembodiments, additional optional steps can be performed.

Optional Step: Keep Vein Open (KVO)

Thrombosis and catheter occlusion are known problems encountered duringuse of an IV system, such as when the fluid flow is stopped for a periodof time or flows at a too slow rate. For example, thrombi in, on and/oraround the catheter 12, such as at the catheter's orifice 12 b can causean occlusion. Occlusion of the catheter can require insertion of a newcatheter in another location. It is known that a slow flow of IVsolution (e.g., saline or calibration fluid; with or without heparin)can prevent catheter occlusion due to thrombosis. This procedure is knowas keep vein open (KVO).

In general, to infuse a fluid into a host, the infusion device mustovercome the host's venous and/or arterial pressure. For example, duringinfusion of a hydration fluid, the IV bag is raised to a height suchthat the head pressure (from the IV bag) overcomes the venous pressureand the fluid flows into the host. If the head pressure is too low, someblood can flow out of the body and in to the tubing and/or bag. Thissometimes occurs when the host stands up or raises his or her arm, whichincreases the venous pressure relative to the head pressure. Thisproblem can be encountered with any fluid infusion device and can beovercome with a KVO procedure. KVO can maintain sufficient pressure toovercome the host's venous pressure and prevent “back flow” of bloodinto the tubing and/or reservoir.

In some embodiments, the flow control device 604 can be configured toperform a KVO step, wherein the fluid flow rate is reduced (but notcompletely stopped) relative to the calibration and/or wash flow rates.In preferred embodiments, the KVO flow rate is sufficient to prevent thecatheter 12 from clotting off and is relatively lower than the flow rateused in step one (above). In preferred embodiments, the KVO flow rate issufficient to overcome the host vessel pressure (e.g., venous pressure,arterial pressure) and is relatively lower than the flow rate used instep one (above). In some embodiments, the KVO flow rate is from about0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06,0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004,0.003, 0.002 or 0.001 ml/min or less to about 1.0, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 ml/min or more. In some preferredembodiments, the KVO flow rate is from about 0.02 to about 0.2 ml/min.In some more preferred embodiments, the KVO flow rate is from about 0.05ml/min to about 0.1 ml/min). In some embodiments, the KVO flow rate isless than about 60%, 50%, 40%, 30%, 20%, or 10% of the calibrationand/or flush flow rate(s). In some embodiments, the KVO step isperformed for from about 0.25 minutes or less to about 20 minutes ormore. In preferred embodiments, the solution 602 a flows at a rate suchthat the temperature of the solution 602 a substantially equilibrateswith the temperature of the tissue surrounding the in vivo portion ofthe catheter 12. Advantageously, equilibrating the solution 602 atemperature with that of the surrounding tissue reduces the effect oftemperature on sensor 14 calibration and/or sample measurement, therebyimproving sensor accuracy and consistency. In some embodiments, the KVOstep can be incorporated into one or more of the flow control devicesteps of operation described elsewhere herein, including steps one andtwo, and the flush step, above.

The KVO step can be executed in one or more ways. In some embodiments,the flow control device 604 can be configured to move to at least oneaddition position, wherein the tube 606 is partially pinched. Forexample, the flow control device 604 is configured to move to a positionsuch that the pinch point 808 is partially closed/open. For example, inthe embodiment shown in FIGS. 8A through 8C, the flow control device 604can be moved forward somewhat past position 812, such that the roller802 causes the tube 606 to be partially pinched. In another example, theflow control device 604 can be moved backwards somewhat behind position810, such that the roller 802 again causes the tube 606 to be partiallypinched. In preferred embodiment, the amount of pinch can be adjustedsuch that the desired KVO flow rate can be achieved. In some alternativeembodiments, KVO is performed by moving the flow control device betweenpositions 810 and 812 (e.g., see FIG. 8A) at a reduced speed, such thatthe flow rate is from about 0.1 μl/min or less to about 0.5 ml/min ormore. In some embodiments, the system is configured such that the timeof movement between the first and second discreet positions is fromabout 0.25 to 30 seconds, preferably from about 5 to 15 seconds. In somepreferred embodiments, the tubing is pinched fully closed (e.g., betweenstructures 802 and 806) during the movement from position 810 and 812(e.g., see FIG. 8A). In some preferred embodiments, after the flowcontrol device reaches position 812, the flow control device flips overthe top and back to position 810 (e.g., see FIG. 8C) at a substantiallyrapid speed that the flow rate remains substantially unchanged. In aneven further embodiment, during the KVO step the flow control devicealternates between the slow and fast movements at least two times, suchthat the KVO step lasts a period of time.

In some circumstances, signal artifacts can occur due to the location acatheter is implanted and if the host has moved his or her arm (wherethe catheter is implanted/inserted) to certain positions (e.g., holdinghis or her arm up, vertically and/or hanging down). While not wishing tobe bound by theory, it is believed that these signal artifacts can arisebecause femoral veins are relatively small (e.g., 1-2 mm diameter), andin some circumstances an inserted catheter can block the flow of atleast some incoming blood, such that the incoming blood is “diverted”around the implantation site by flowing through adjacent alternativeveins and/or capillaries. As a result, the blood in the vein containingthe catheter can be diluted for a period of time (e.g., after flushing),which can lead to diluted analyte values, which appear as signalartifacts. As time passes, the dilution of the sample by the salineflush dissipates and undiluted blood samples are collected, which leadsto termination of the signal artifact(s). The way the host holds his orher arm can affect the length of time required for the signal artifactto dissipate. For example, in some embodiments, if the host holds his orher arm at chest level, the vein is filled by blood at a first rate, andthe sample dilution is dissipated within a first time period. If thehost holds his or her arm down low, the blood flows through the vein ata second rate that is faster than the first rate, and the dilution isrelieved sooner (e.g., within a second time period that is shorter thanthe first time period). Conversely, if the host raises his or her armover his or her head, the blood flows into the vein at a third rate thatis slower than the first rate; which results in the dilution dissipatingwithin a third period of time that is longer than the first period oftime.

In some embodiments, the signal artifacts resulting from blocking of thevein at the site of catheter implantation and subsequent sample dilutioncan be substantially eliminated (or reduced/shortened) by reducing thevolume of 0 mg/dl solution used to wash away the 100-mg/dl calibrationsolution, depending upon the volume of the 100 mg/dl calibrationsolution used to calibrate the sensor. For example, in some embodimentsa 0.5×, 1×, 2×, 3×, 4×, 5×, 6×, 7×, 8×, 9×, 10× (or greater) volume ofthe 0-mg/dl solution can be used to sufficiently wash out the volume 100mg/dl calibration solution. In some embodiments, wherein a sufficientlysmall volume of 100 mg/dl solution is used during calibration, theflushing can be done at the KVO rate. In some embodiments, signalartifacts are prevented by using smaller volumes of calibration/washfluids but switching more frequently between the fluids.

Maintaining Patency During a Sensor Session

In some embodiments, the analyte sensor is implanted in the host (e.g.,via a vascular access device) for an extended period of time. Forexample, in some embodiments, a sensor session can last 3, 5, 7, 10, 21,30 or more days. As used herein, the term “sensor session” is a broadterm and refers without limitation to the period of time of sensor isapplied to (e.g., implanted in) the host and is being used to obtainsensor values. For example, in some embodiments, a sensor sessionextends from the time of sensor (e.g., including implanting the vascularaccess device) implantation to when the sensor is removed. During thisperiod of time, the vein's condition can deteriorate, such that veinand/or vascular access device is no longer patent (e.g., freely open,not occluded), and the system can no longer function optimally. Whilenot wishing to be bound by theory, it is believed that patency can besubstantially maintained during a sensor session by metering areference/calibration solution through the vascular access device asufficient amount of time (e.g., a percentage of the duration of thesensor session). As used herein, the phrase “a sufficient amount” is abroad term and refers without limitation to an amount that provides adesired function. For example, a sufficient amount can be a sufficientamount of time, a sufficient amount of fluid volume, and the like. Insome embodiments, a sufficient amount can be expressed numerically, suchas a percent (%), a volume, a weight, a period of time (e.g., minutes,hours, days, months), and the like. For example, in some embodiments,the flow control device is configured to meter a sufficient amount of areference solution (e.g., through the vascular access device) such thatthe analyte sensor contacts the reference solution at least about 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the time during asensor session. It is generally preferred that the analyte sensorcontacts the reference solution from about 50% to about 80%, 85%, 90% or95% of the time during a sensor session In some embodiments, the sensoris located in or on the vascular access device and the flow controldevice meters the reference solution through the vascular access devicefor a sufficient amount of time (e.g., a portion of the sensor session),with a sufficient flow rate (e.g., from about 0.05 ml/min to about 0.5ml/min, preferably about 0.1 ml/min) that the vascular access deviceremains patent during a sensor session. Advantageously, the flow rate issufficient to maintain a patent vessel without infusing excess fluid. Ina preferred embodiment, the vascular access device remains patent duringa sensor session of at least about 1, 3, 5, 7, 10, 15, 20, 25, or 30days, or longer. In one exemplary embodiment, the flow control device isconfigured to meter the reference solution through the vascular accessdevice for at least about 50% of a sensor session, at a flow rate fromabout 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07,0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005,0.004, 0.003, 0.002 or 0.001 ml/min or less to about 1.0, 1.1, 1.2, 1.3,1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 ml/min or more, such that thevascular access device remains patent during a sensor session of atleast about 5 days. In another exemplary embodiment, the flow controldevice is configured to meter the reference solution through thevascular access device for at least about 65% of a sensor session, at aflow rate from about 0.001 ml/min to about 2.0 ml/min, such that thevascular access device remains patent during a sensor session of betweenabout 5 days and about 30 days. In still another exemplary embodiment,the flow control device is configured to meter the reference solutionthrough the vascular access device for between about 50% and about 80%of a sensor session, at a flow rate from about 0.001 ml/min to about 2.0ml/min, such that the vascular access device remains patent during asensor session of at least about 30 days.

Preventing Sensor Biofouling During a Sensor Session

As discussed above, sensor sessions can last from about 3 days to 30 ormore days. During this period of time, the sensor is repeatedly exposedto (contacted with) a bodily fluid (e.g., blood). In some circumstances,during sensor exposure to blood, some blood components/material, such asbut not limited to proteins, lipids, carbohydrates and cells, can“stick” to the sensor, such that a layer of this material coats at leastpart of the sensor and the sensor can no longer function accurately.This process of blood components sticking to the sensor and disruptingthe sensor's function is generally referred to as “biofouling.” Whilenot wishing to be bound by theory, it is believed that biofouling can besubstantially reduced and/or eliminated by limiting the length of timethe sensor is exposed to blood and/or by maintaining the sensor in areference solution (or saline) a substantial portion of the sensorsession, whereby sensor accuracy is maintained throughout the sensorsession. Washing the sensor is described in detail in the sectionentitled “Maintaining Patency During A Sensor Session.”

As a non-limiting example, in some embodiments, the flow control deviceis configured to meter the reference solution, such that the referencesolution contacts the sensor a substantial amount of time such thatbiofouling does not occur for at least about 3 days of sensor use. Forexample, the sensor can be contacted with the reference solution about50%, 60%, 70%, 80%, 90%, or 95% of the sensor session duration. Inpreferred embodiments, the system is configured such that biofoulingdoes not occur for at least about 7, 10, 21, 30 or more days of sensoruse.

In one exemplary embodiment, wherein the sensor is located in or on avascular access device, the system includes a flow control deviceconfigured to meter a reference solution through the vascular accessdevice for a sufficient amount of time and with a sufficient flow ratethat substantially no biofouling of the sensor occurs during a sensorsession of at least about 3 days. For example, in some embodiments, theflow control device meters the reference solution through the vascularaccess device for at least about 50% of a sensor session, at a flow ratefrom about 0.001 ml/min to about 2.0 ml/min, such that substantially nobiofouling of the sensor occurs during a sensor session of at leastabout 5 days. In another exemplary embodiment, the flow control devicemeters the reference solution through the vascular access device for atleast about 65% of a sensor session, at a flow rate from about 0.9, 0.8,0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04,0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002or 0.001 ml/min or less to about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,1.8, 1.9 or 2.0 ml/min or more, such that substantially no biofouling ofthe sensor occurs during a sensor session of between about 5 days andabout 30 days. In still another exemplary embodiment, the flow controldevice meters the reference solution through the vascular access devicefor between about 50% and about 80% of a sensor session, at a flow ratefrom about 0.001 ml/min to about 2.0 ml/min, such that substantially nobiofouling of the sensor occurs during a sensor session of at leastabout 30 days.

Alternative Flow Control Device Configurations

As disclosed above, the flow control device 604 can be configured avariety of ways, which can require modifications to one or more of thesteps of operation described above. For example, in some embodiments,the flow control device 604 can be configured to include a simple pinchvalve, wherein the valve can be configured to open, close or partiallyopen. In some embodiments, the flow control device 604 can be configuredto include a non-linear rolling pinch valve, wherein the roller can moveback and forth between opened, closed and partially opened positions,for example.

In some embodiments, the flow control device 604 can include one roller802 (e.g., first structure) attached to an axle 804 and configured topress against a curved surface 806 (e.g., second structure), such thatwhen the roller 802 is pressing against the curved surface 806 at orbetween positions 810 and 812, the tubing 606 is pinched completelyclosed and the flow control device 604 moves the roller 802 forward(e.g., toward the host). In one exemplary embodiment, the flow controldevice 604 can be configured to perform step one (above, contacting thesensor 14 with solution 602 a) by moving the roller 802 forward (e.g.,rotating from position 810 to 812, see FIG. 8A), thereby causingsolution 602 a to flow over the sensor 14. In some embodiments, the flowcontrol device 604 is configured to perform step two (contacting thesensor 14 with sample) by moving the roller 802 backwards (e.g.,rotating from position 812 to 810, see FIG. 8B), thereby causing blood814 to enter the catheter 12 and contact the sensor 14. Additionally,the flow control device 604 can be configured to perform a wash or KVOstep by moving the roller 802 forward (from position 810) past position812 and around the axle 804 until position 810 is again reached aplurality of times sequentially (e.g., see FIG. 8C). In a furtherexample, the flow control device 604 includes two, three or more rollers802 arranged about axle 804, such as by attachment to an oblong bodyattached to the axle. In some embodiments, the flow control deviceincludes a plurality of rollers arranged about the axle, wherein theflow control device performs KVO by rotating the rollers about the axlea plurality of times, to substantially continuously push (e.g., for aperiod of time) the solution forward into the host.

In one alternative embodiment, back flow is substantially stopped,blocked and/or prevented by incorporation of a one-way,pressure-controlled valve into the system, such as at or adjacent to thecatheter or sensor connector, whereby fluid can flow into the host onlywhen fluid pressure (e.g., head pressure) is applied to thereservoir-side of the valve. In other words, fluid can only flow in thedirection of the host (e.g., toward the host), not backwards towards thereservoir. In some embodiments, the valve is a two-way valve configuredsuch that the pressure required to open the valve is greater than thevenous pressure, such that back flow is substantially prevented.

The preferred embodiments provide several advantages over prior artdevices. Advantageously, the movement of the solution 602 a and sampleoccur at a metered rate and are unaffected by changes in head pressure,such as but not limited to when the host elevates his or her arm or getsup to move around. Also, sample loss to the host is minimized, first byreturning all collected samples to the host; and second by substantiallypreventing back-flow from the host (e.g., into the tubing or reservoir)with a “hard stop” (e.g., a point beyond which the flow control devicecannot move fluid into or out of the host). For example, in onepreferred embodiment, the flow control device can be configured todeliver no more than 25-ml of solution to the host per hour. In anotherexemplary embodiment, the flow control device can be configured to drawback no more than 100 μl of blood at any time. Advantageously, the flowrate of solution 602 a and sample 814 is carefully controlled, such thatboth the sample 814 and the solution 602 a remain substantiallyundiluted. Additionally, the solution 602 a warms to the host's localbody temperature, such that the integrated sensor system 600 issubstantially unaffected by temperature coefficient and sensor 14accuracy is increased.

FIGS. 10A through 10D illustrate one exemplary embodiment of a flowcontrol device 604 configured and arranged for use with a vascularaccess device (e.g., catheter and/or fluid coupler) and analyte sensor,such as those described elsewhere herein. The flow control deviceincludes a groove 803 configured to receive the tubing assembly therein606 a. In some embodiments, the groove 803 is configured and arranged toreceive the tubing (of the tubing assembly) in a substantially straightconfiguration. The groove 803 intersects with a valve roller mechanism,which includes an oblong body comprising two rollers 802 (e.g.,corresponding to the first structure 802, which is attached to axle 804of the embodiment shown in FIGS. 8A-8C) and a compression surface 806(e.g., corresponds to the second structure 806 of the embodiment shownin FIGS. 8A-8C). The valve includes at least two valve positions, agravity flow valve position and a controlled-flow valve position. FIG.10C illustrates one embodiment of the gravity flow valve position, inwhich the rollers 802 are positioned such that they do not compress,pinch and/or occlude the tubing, such that fluid flowing from the IV bagcan flow freely through the tubing 606 b in the valve. At gravity flow,the rate of fluid flow through tubing 606 b is from about 600-ml/hr(e.g., about 10 ml/min) to about 700-ml/hr (e.g., about 1.2 ml/min),depending upon the height of the IV bag 602.

FIG. 10D illustrates one embodiment of the controlled-flow valveposition, in which a roller 802 is positioned such that the tubing 606 b(of the tubing assembly) is pinched between the roller 802 andcompression surface 806 (e.g., pinch point 808 exists), such thatmovement of fluid through the valve is controlled by the rotation of theoblong body (e.g., to which the roller is attached) on its axle. In thecontrolled flow position, the valve is configured and arranged to movefluid forward and/or backward at various rates, depending upon the speedand direction of oblong body rotation on the axle. Flow rates can bepositive (e.g., infusing fluid) or negative (e.g., drawing backfluid/blood) and can range from about −10.0, −9.0, −8.0, −7.0, −6.0,−5.0, −4.0, −3.0, −2.0, 1.0, −0.9, −0.8, −0.7, −0.6, −0.5, −0.4, −0.3,−0.2, −0.1, −0.05, −0.01, 0.0, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 ml/hrto about 20.0, 30.0, 40.0, 50.0, 60.0, 70.0, 80.0, 90.0, 100.0, 110.0,130.0, 150.0, 175.0, 200.0, 225.0, 250.0, 275.0, 300.0, 350.0, 400.0, or450.0 ml/hr or more. Useful flow rates and valve movement between thegravity flow and controlled-flow valve positions are described ingreater detail elsewhere herein with reference to FIG. 10E.

The valve is configured to receive the tubing 606 b (e.g., of the tubingassembly 606 a), such as via groove 803 (e.g., tubing path or channel).One skilled in the art understands that while FIGS. 10A-10D illustrategroove 803 running from the top of the valve to the bottom (e.g., on theface or front of the device), additional configurations are possible.Namely, the groove can be located in any direction or orientation alongany surface of the device (e.g., top, bottom, sides), or the groove canbe enclosed within the device, such as within a housing configuredcover, supports and/or limit access to the valve, a portion of thetubing, and/or accessory devices. For example, in some embodiments, thevalve is located within a housing, such that the valve and the tubingassembly are accessed via a door. The housing can include one or moreorifices, such that the tubing can intersect (e.g., pass through) a wallof the housing and be installed into the valve within the housing. Insome embodiments, the door includes a locking mechanism, such as but notlimited to a mechanical key or electronics code key (e.g.,electronically, such as such as to prevent tampering with the device).

The valve is configured for uni-directional, releasable installation ofthe tubing assembly 606 a (also referred to herein as “tubing set”),such that the tubing assembly's elastic central portion 606 b (e.g.,tubing) is received by the groove and the tubing's fluid connectors 606c, 606 d are disposed at opposite ends of the groove, in someembodiments. In some embodiments, the groove is sized to be somewhatlonger than the central portion of the tubing assembly, such that thetubing (of the tubing assembly) must be stretched (e.g., by grasping theconnectors and pulling in opposite directions) prior to and/or duringinstallation into the channel/groove. After installation, the connectorends are released, such that the tubing relaxes. However, the tubingremains stretched (e.g., relative to its un-stretched state prior toinstallation) after installation. Maintaining the tubing in a stretchedstate can help maintain the tubing assembly within the valve without thetubing moving, twisting, kinking or falling out of the valve. The tubingassembly is configured for fluid communication with an IV bag (e.g.,fluid reservoir 602), such as via the first connector 606 c, and withthe circulatory system of the host, such as via fluid connection of thesecond connector 606 d to a catheter implanted in the host.

In some embodiments, the valve is configured and arranged to receive thetubing assembly in only one orientation. For example, in someembodiments, the valve and the tubing assembly are configured andarranged to releasably interlock such that a portion of the valvemechanically interlocks with a portion of the tubing assembly. Forexample, in some embodiments, the valve includes the first portion of amechanical interlock and the tubing assembly includes the second portionof the mechanical interlock. For example, in FIG. 10A, the valveincludes a female interconnection 809 sized and shaped to releasablyreceive and engage the tubing assembly's second connector 606 d (whichin this embodiment includes rectangular wings that project from a femaleLeur connector). As is appreciated by one skilled in the art, the systemcan be configured such that the mechanical interlock is located ateither end of the groove 803 (e.g., such that connector 602 forms aportion of the mechanical interlock, instead of connector 606 d) or atsome point in between. Advantageously, the mechanical interlockreinforces uni-directional installation of the tubing assembly, as wellas helping to maintain the tubing within the valve in the correctconfiguration.

In some embodiments, the mechanical interlock is configured to engage aparticular vascular access device (e.g., a specific type of catheter),wherein the mechanical interlock and/or the vascular access device areconfigured and arranged to provide additional structural and/orelectronic identification information, to ensure and/or to promote theuse of the correct vascular access device (e.g., catheter, fluidcoupler) and/or to enable the correct selection of a flow profileassociated with the vascular access device. For example, in oneembodiment, the mechanical interlock is configured and arranged toidentify (to the flow control device) the type of vascular access deviceand/or sensor being used (such as for identification of the flow profilethat corresponds with the selected catheter). In some embodiments, themechanical interlock provides identification information to the flowcontrol device, wherein the identification information is associatedwith the vascular access device and a corresponding flow profile. Inpreferred embodiments, the identification information is providedautomatically, such as by a mechanical structure of the vascular accessdevice. In some embodiments, the identification information is providedby electronics associated with the vascular access device. For example,in one embodiment, the catheter includes the electronics that providethe identification information. In another embodiment, the fluid couplerincludes the electronics that provide the identification information. Inone exemplary embodiment, the system is configured to select a flowprofile associated with a mechanical interlock (e.g., the identificationinformation), when the mechanical interlock is engaged (e.g., thevascular access device is connected to the tubing assembly and/or theflow control device). Additional a mechanical interlock between thesecond end of the tubing assembly and the vascular access device isconfigured and arranged to prevent twisting of the connection betweenthe tubing assembly and the vascular access device.

In some embodiments, uni-directional tubing installation is importantfor aligning functional portions of the valve with functional portionsof the tubing assembly. For example the tubing assembly includes anelastic tubing portion configured to be manipulated by the valve (e.g.,pinched, etc.). In another example, the valve can include one or morefunctional elements, such as but not limited to a bubble detector 805(located along groove 803 and configured and arranged to detect bubblesin the tubing 606 b) and an electronic solenoid 807 (e.g., configured toalign with the free flow mitigation device 606 e of the tubing and toopen the free flow mitigation device, see “Free Flow Mitigation”).

Referring now to FIGS. 10C-10D, in some embodiments, the flow controldevice includes a flow profile comprising two valve positions, a gravityflow position and a controlled flow position. Flow profiles aredescribed in detail with respect to FIG. 10E. In preferred embodiments,the valve is configured and arranged to move between the gravity flowand controlled flow valve positions, such that when the valve is in thegravity flow position, tubing received therein is in a substantiallystraight (e.g., linear) configuration and when the valve is in thecontrolled flow positions the tubing received therein is in asubstantially non-linear configuration. As a non-limiting example, FIG.10C illustrates a gravity flow position, in which the valve roller (e.g.the first structure 802, a roller attached to an oblong rotating memberor body configured to engage curved surface 806) is oriented (e.g.,positioned) such that there is no pinch point in the tubing (e.g., thetubing is not compressed between the first and second structures). Inthis embodiment, the tubing is in a substantially straight (e.g.,un-bent, unpinched, and/or not occluded) configuration when the valve isin the gravity flow position. In the gravity flow position, IV fluid canflow freely through the vascular access device and into the host,simultaneously flushing and/or washing the analyte sensor. FIG. 10Dillustrates the valve in a controlled flow position. In the controlledflow position, the rotating member 802 is rotated on its axle to anorientation such that the tubing 606 b is non-linear (e.g., curved,bent) and a pinch point 808 (e.g., between the rotating member 802 andthe compression surface 806) prevents fluid flow. The valve isconfigured to rotate the roller valve on an axle, such that the pinchpoint can be moved along the compression surface. Thus, the flow controldevice moves through a plurality of controlled flow positions. Movementof the valve is similar to the valve movements described with referenceto FIGS. 8A-8C. Accordingly, when the tubing is in a bent configuration,the pinch point 808 is pushed forward (e.g., along surface 806) as therotating member moves forward, and such that an amount of fluid ispushed forward (e.g., infusion fluid, calibrant, sample) through thetubing, as described with reference to FIG. 8A. Similarly, when thetubing is in a bent configuration, the pinch point 808 is pushedbackwards (e.g., along surface 806) as the rotating member moves inreverse, such that an amount of fluid is drawn back (e.g., infusionfluid, calibrant, sample) through the tubing, such that a sample isdrawn back into the vascular access device and the analyte sensor isbathed in the sample.

FIG. 10E is a graph illustrating an exemplary flow profile, in oneembodiment. In preferred embodiments, the flow control device (e.g., thevalve) includes a flow profile that is configured and arranged to directthe movements of the flow control device (e.g., between the free flowand controlled flow valve positions, see FIGS. 10C-10D), such that theanalyte sensor is alternately bathed in samples and washed by theinfusate (e.g., IV fluid, calibrant solution, a medicament solution, andthe like). Referring to the exemplary flow profile depicted in FIG. 10E,time is shown on the X-axis and flow rate (e.g., the rate of fluid beingmoved through the valve) is shown on the Y-axis. Because this is ageneric flow profile, for discussion purposes only, the Y-axis isrelative and thus has no 0-ml/hr flow rate depicted. A specific flowprofile can include a 0-ml/hr flow rate, as well as positive (e.g.,valve moving forward) and negative (e.g., valve moving backwards) flowrates. The flow profile includes one or more phases (e.g., phases X, Yand Z); wherein each phase is configured to infuse an amount of fluid,to draw back an amount of sample and/or to hold an amount of fluid(e.g., infusion fluid and/or drawn-back sample) stagnant (e.g.,substantially still). In general, a phase is associated with a function,such as but not limited to drawing back a sample (e.g., blood) such thatthe analyte sensor is bathed in the sample, returning the used sample tothe host, washing the analyte sensor (e.g., with solution), calibratingthe sensor, maintaining vessel patency, KVO, infusing a hydration fluid,infusing an amount of medicament (e.g., responsive to analyte sensordata and/or to a criterion and/or protocol), and the like. In general, aphase of the flow profile can include one or more flow rates, each ofwhich can last various periods of time. A rate can be selected dependingupon the function of the phase of the flow profile, the content of theinfusion fluid, the size of the vascular access device (e.g., cathetersize, sample size, etc.), a medication protocols, and the like.

As a non-limiting example, the flow profile depicted in FIG. 10Eincludes three phases (e.g., X, Y, and Z). Phase X includes two flowrates, Rate A and gravity flow (GF). Phase Y includes a second rate(Rate B), which is lower (e.g., slower) than Rate A. Phase Z contains athird rate (Rate C), which is lower than both Rates A and B. At Rates A,B and C, the valve is in a controlled flow valve position. When thevalve is in a controlled flow position, it can be stationary (e.g.,0-ml/hr flow rate) or it can move through a plurality of positions inwhich the tubing is pinched between the roller 802 and the compressionsurface 806. While not wishing to be bound by theory, one can consideran infinite number of controlled flow positions to exist, wherein thevalve creates pinch point 808 by compressing the tubing between theroller 802 and compression surface 806. Similarly, an infinite number ofpinch points can exist along the compression surface, provided that thevalve is in a controlled flow position. The valve is configured to moveat a plurality of speeds, such that the valve can move the pinch pointat a plurality of speeds (faster/slower), such that the desired (e.g.,programmed and/or re-programmed) flow rates are achieved. For example,fluid can be infused at rates from about 0.0, 0.001, 0.01, 0.1, 0.25,0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0,10.0 ml/hr to about 20.0, 30.0, 40.0, 50.0, 60.0, 70.0, 80.0, 90.0,100.0, 110.0, 130.0, 150.0, 175.0, 200.0, 225.0, 250.0, 275.0, 300.0,350.0, 400.0, or 450.0 ml/hr or more. In another example, sample can bedrawn back at rates from about −10.0, −9.0, −8.0, −7.0, −6.0, −5.0,−4.0, −3.0 ml/hr to about −2.0, −1.0, −0.9, −0.8, −0.7, −0.6, −0.5,−0.4, −0.3, −0.2, −0.1, −0.05, −0.01 or −0.001 ml/hr or less. In someembodiments, when the valve is in the controlled flow position, the flowrate is from about 0.5-ml/hour to about 4.0-ml/hr. In some embodiments,a phase of the flow profile can include two, three, four or more rates.In some embodiments, a phase can include a period of gravity flow (e.g.,GF), during which the valve is moved to the gravity flow position, whichis discussed in greater detail below. In some embodiments, the one ormore rates are optimized to achieve the function of the phase relativeto a medical protocol. For example, during a wash phase, a slower flowrate can be used if the infusion solution contains heparin, as comparedto the flow rate necessary to sufficiently clean the sensor of bloodcells when a non-heparinized infusion solution is used. As anotherexample, if the infusion solution contains a medicament, the flow rateof a wash phase can be selected to optimize sensor cleaning while stillinfusing the desired amount of medicament into the host. In stillanother example, a slower flow rate can be chosen to flush the sensorand return the sample to a neonatal host, due to the small lumen size ofthe catheters used in such tiny hosts, such that, for example, excessiveamounts of fluid are not infused into the host. In yet another example,during a calibration phase, the calibrant can be slowly infused (e.g.prior to and/or during measurement of the calibration solution), suchthat the temperature of the calibration fluid equilibrates with thehost's body temperature, as described elsewhere herein. In still anotherexample, during a measurement phase, a sample can be drawn back at arate selected to maintain the temperature of the sample, to preventrupture of blood cells within the sample, and/or to optimize sensorfunction.

The flow profile can include periods of gravity flow (GF), during whichthe valve is in the gravity flow valve position and fluid 602 a can flowfreely through the valve (e.g., through the tubing received by thevalve). The rate of gravity flow is dependent upon the affect of gravityon the infusion fluid, and thus depends in part on the height of the bag602. For example, the bag can be located relatively higher or lower,with respect to the valve, the floor and/or the host. If the bag ishigher, the flow rate will be relatively faster. If the bag is lower,the flow rate will be relatively slower. In some embodiments, gravityflow rates range from about 600, 630 or 650-ml/hour to about 670 or700-ml/hour or more. In some embodiments, when the valve is in thegravity flow valve position, the flow rate is at least about 600-ml/hr.In some embodiments, the system is configured such that the analytesensor is flushed (e.g., washed, cleaned, cleaned) by the solution whenthe valve is in the gravity flow valve position. For example, in someembodiments, gravity flow removes blood cells or other blood componentsfrom the sensor and/or the lumen of the vascular access device moreefficiently that other (e.g., lower) flow rates.

In some embodiments, washing of the sensor is optimized by setting aratio of gravity flow rate to controlled flow rate, such as viaprogramming the flow profile to provide the flow rates. For example, insome embodiments, the ratio of gravity flow (e.g., a first flow rate) tocontrolled flow (e.g., a second flow rate) is at least about 10:1,wherein, the rate of gravity flow lasts 10-times greater than thecontrolled flow rate. In some embodiments, the ratio of the gravity flowrate to the controlled flow rate is at least about 2:1, 3:1, 4:1, 5:1,6:1, 7:1, 8:1 or 9:1. In some embodiments, the ratio of the gravity flowrate to the controlled flow rate is from at least about 12:1, 15:1,20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1 or 100:1 to at leastabout 125:1, 150:1, 175:1, 200:1, 250:1, 300:1, 350:1, 400:1, 450:1, or500:1 or greater. In some embodiments, the ratio of the gravity flowrate to the controlled flow rate is optimized for sensor washing. Forexample, the ratio is optimized such that the washed sensor'smeasurement of the current sample is substantially unaffected by thepresence of components of the previous blood sample. For example, insome embodiment, the optimal ratio of the gravity flow rate to thecontrolled flow rate, for sensor washing, is 10:1. In some embodiments,the optimal ratio (of gravity flow to controlled flow) for sensorwashing is at least about 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or 9:1. Insome embodiments, the ratio of the gravity flow rate to the controlledflow rate is from at least about 12:1, 15:1, 20:1, 30:1, 40:1, 50:1,60:1, 70:1, 80:1, 90:1 or 100:1 to at least about 125:1, 150:1, 175:1,200:1, 250:1, 300:1, 350:1, 400:1, 450:1, or 500:1 or greater. In someembodiments, a period of gravity flow is included in a phase of the flowprofile, such as a wash or flush phase, or in a phase configured toinfuse a programmed amount of infusion solution (e.g., for hydration,for nutrition and/or to deliver an amount of medicament). In someembodiments, the flow profile is configured to cycle between two or moreflow rate ratios. In some embodiments, the ratio of flow rates isassociated with the configuration of the system. For example, a systemconfiguration for use in an adult host will have different flow profilerequirements than a system configured for use in a pediatric host. Inanother example, a system configured access of the circulatory systemvia an artery will have different flow profile requirements than asystem configured for access via a vein. In yet another example, asystem having the sensor extend into a catheter's lumen may be havedifferent flow profile requirements than a system having a sensorlocated in a fluid coupler.

Returning to FIG. 10E, the flow profile can be configured differently,depending upon the system configuration, the type of host, and the like.For example, the flow profile can include more or fewer phases. Inanother example, Phase X can include one or more additional flow rates,or it could consist of only Rate A or only GF. In another example, RateB can be slower or faster than depicted, including even slower than RateC or greater than Rate A. In another example, Phase Y can includeadditional periods of faster and/or slower rates and/or one or moreperiods of GF. Rate C can be even slower, or it could be faster. If RateC is a negative rate, then sample is being drawn back and can be drawnback at slower (less negative) or faster (more negative) speeds. Inanother example, a phase can include two or more flow rates that arealternated intermittently and/or periodically throughout the phase. Inyet another example, a phase can include a flow rate of about 0.0ml/min, wherein the fluid and/or sample is held substantially stagnantfor a period of time.

In some embodiments, at least a portion of a flow profile can berepeated. For example, two or more phases can be repeated for a periodof time, such as but not limited to a period of time lasting from about1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours to about 0.75, 1, 2, 3, 4or more days. In some embodiments, the two or more phases of the flowprofile are repeated until a criterion is met and/or exceeded (e.g.,until a certain period of time has passed, until an amount of medicamentis infused, until the host's blood analyte level falls within apreprogrammed range of concentrations, until a caretaker responds to analarm by pressing a button on the user interface, and the like). In someembodiments, all of the phases of the flow profile are repeated, such asin a cyclical manner, such as until the end of the sensor session (e.g.,when the sensor is removed from the host and/or the system is turnedoff). In some embodiments, the flow profile is configured to be pausedand/or interrupted, such as during transfer of the host from hishospital room to another location for a procedure, for example.

In some embodiments, the flow profile is configured to be responsive tothe analyte level measured/generated by the sensor. For example, theflow profile can be configured to use one or more optional phases, whichcan include one or more alternative flow rates, when the analytemeasured meets/exceeds a criterion. For example, in some embodiments,the infusion solution includes a medicament. In some embodiments, theflow profile is configured to meter the flow of the medicament solutionbased at least in part on a measured analyte concentration. In oneexemplary embodiment, the sensor includes a glucose sensor, the IVsolution contains insulin, and the flow profile is configured to infusean amount of the insulin solution in response to the host's glucoselevel. For example, the flow profile can be configured to infuse a lowamount of insulin continuously (e.g., a basal amount) and when thehost's blood glucose exceeds a programmed range, the flow profile canincrease the rate of infusion for a period of time, such as until thehost's glucose returns to the range (e.g., a bolus amount). In someembodiments, the amount of medicament (e.g., the insulin solution) to beinfused is calculated by the processor module, responsive to the sensordata. In some embodiments, the processor module includes at least aportion of the flow profile. In some embodiments, the flow profileincludes an optional phase, such as but not limited to an infusionphase, configured to infuse an amount of medicament. For example, insome embodiments, the processor module includes a medicament infusionphase configured to infuse an amount of insulin sufficient to return thehost's blood glucose to a programmed range (e.g., between 80-120 mg/dlglucose). In some exemplary embodiments, the flow profile can beprogrammed (e.g., re-programmed), such as by the processor module (e.g.,responsive to at least one criterion), such that a medicament infusionphase is added to the flow profile for one or more cycles. In someembodiments, the flow profile includes selectable sub-profiles, whichcan be automatically selected by the flow profile responsive to one ormore criteria and/or selectable and/or programmable by a caretaker. Insome embodiments, the flow profile includes a menu of selectable flowprofiles (e.g., two or more), from which a user can select one to usewhen applying the system to a host (e.g., installation, set up). Forexample, in some embodiments, a user can select the flow profile to usefrom the menu, depending upon host physical properties, a drug to beinfused, certain medical protocols, and the like.

As described in the section entitled “Fluids,” in some embodiments theinfusion solution is a saline solution formulated for infusion into thehost. In some embodiments, the infusion solution can contain an amountof the calibrant. For example, if the sensor is a glucose sensor, theinfusion solution can contain an amount of glucose (e.g., 50, 75, 100,125, 150, 175, or 200 mg/dl glucose or more) suitable for calibratingthe glucose sensor. This type of solution may be referred to as a“calibration solution.” In some embodiments, the medicament solution caninclude a calibrant. For example, if the sensor is a glucose sensor andthe medicament is insulin, the insulin solution can also containglucose. Alternatively or additionally, the calibration solution and themedicament solutions can be provided separately, such at in separate IVbags. Accordingly, in some embodiments, the system is configured toswitch some one IV bag to the other (e.g., from the calibration solution(e.g., glucose) to the medicament solution (e.g., insulin) and viceversa) accordingly to the flow profile. In other embodiments, the systemincludes as mixing valve configured and arranged to mix the medicamentsolution and the calibrant solution, wherein a ratio of medicamentsolution to calibrant solution is based at least in part on a measuredanalyte concentration. For example, if the host's blood glucose exceedsthe programmed range, then the flow profile can respond by directingmixing an amount of the insulin solution into the calibration solutionbeing infused, wherein the amount of insulin is sufficient to return thehost's glucose to the programmed range. In some embodiments, the flowcontrol device is further configured and arranged for a piggybackconnection with a medicament delivery device, such as a bedside orambulatory infusion pump. In preferred embodiments, the piggybackconnection includes at least one check valve. Check valves can beconfigured to provide a variety of functions. For example, in someembodiments, the check valve is configured to prevent backflow into thepiggybacked medicament delivery device, such as flow of calibrationsolution into the medicament delivery device's medicament reservoir. Inother embodiments, the check valve is configured to prevent inadvertentdraining of the medicament reservoir into the host, such as when thesystem is shut off. Descriptions of some medicament infusion devicessuitable to piggyback with the present system can be found in U.S.Patent No. U.S. Pat. No. 4,685,903, U.S. Pat. No. 4,898,578, U.S. Pat.No. 4,925,444, U.S. Pat. No. 5,158,437, U.S. Pat. No. 5,219,279, U.S.Pat. No. 5,207,642, U.S. Pat. No. 5,248,300, U.S. Pat. No. 5,321,392,U.S. Pat. No. 5,496,273, U.S. Pat. No. 5,522,798, U.S. Pat. No.5,482,446, U.S. Pat. No. 5,547,470, U.S. Pat. No. 5,551,850, U.S. Pat.No. 5,630,710, U.S. Pat. No. 5,681,285, U.S. Pat. No. 5,685,844, U.S.Pat. No. 5,745,378, U.S. Pat. No. 6,231,320, U.S. Pat. No. 6,231,560,U.S. Pat. No. 6,269,340, U.S. Pat. No. 6,544,229, U.S. Pat. No.6,648,821, U.S. Pat. No. 6,817,990, U.S. Pat. No. 6,692,457, U.S. Pat.No. 6,985,870, U.S. Pat. No. 7,018,361, U.S. Pat. No. 7,109,878, U.S.Pat. No. 7,204,823, U.S. Pat. No. 7,402,153, U.S. Pat. No. 7,417,729,U.S. Patent Publication No. US-2007-0060871-A1, U.S. Patent PublicationNo. US-2007-0112298-A1, U.S. Patent Publication No. US-2007-0213657-A1,U.S. Patent Publication No. US-2007-0299389-A1, U.S. Patent PublicationNo. US-2008-0033357-A1, U.S. Patent Publication No. US-2008-0097326-A1,U.S. Patent Publication No. US-2008-0103447-A1, U.S. Patent PublicationNo. US-2008-0154177-A1, U.S. Patent Publication No. US-2008-0147050-A1,U.S. Patent Publication No. US-2008-0161753-A1, and U.S. PatentPublication No. US-2008-0200897-A1, each of which is incorporated hereinby reference in its entirety.

As described herein, in some embodiments, the flow control deviceincludes an electronic solenoid 805 configured to operate a free flowmitigation device 606 e (e.g., a spring-clip occluder included in thetubing assembly 606 a). A free flow mitigation device is configured andarranged to prevent inadvertent free flow of IV solution into the host,such as during tubing installation and removal, or during powerinterruption to the system. The flow control device and tubing assemblyare configured and arranged such that they are functionally engagedafter the tubing is installed in the vascular access device. Forexample, in FIG. 10A, the free flow mitigation device 606 e and theelectronic solenoid 805 are aligned such that the solenoid can bias(e.g., activate) the spring clip occluder in a non-occluded (e.g.,un-pinched, opened) position, when the system is in operation. Thespring clip occluder is configured and arranged to be engaged by anelectronic solenoid 805 located in the flow control device. In preferredembodiments, the electronic solenoid 807 is configured and arranged suchthat free flow mitigation device returns to an occluded position whenpower is removed, such as when the system is turned off on in the eventof a power outage. In preferred embodiments, the system configured andarranged to control the free flow mitigation device electronically, suchas but not limited to by the flow profile. For example, in oneembodiment, after system installation and/or initiation, the flowprofile electronically controls the electronic solenoid to maintain thespring clip occluder in an opened position. In another embodiment, theflow profile directs the solenoid to activate (e.g., open, biased in thenon-occluded position) the free flow mitigation device during solutioninfusion and/or sample drawback, and to deactivate (e.g., closed, biasin the occluded position) the free flow mitigation device if the systemis paused and/or the system is switched off. In still anotherembodiment, the flow profile includes a phase with a 0-ml/hr (or0-ml/min) flow rate, and the flow profile electronically directs thesolenoid to deactivate the free flow mitigation device during thisphase, and activation (e.g., reactivation) of the free flow mitigationdevice during the other phases of the flow profile. In some embodiments,the flow profile is configured to deactivate the free flow mitigationdevice (e.g., via the electronic solenoid) in response to a fail-safe,such as but not limited to in response to a fail-safe programmed tohandle a fluidics problem or a sensor failure. Fail-safes are describedin detail elsewhere herein.

In some embodiments, the system is configured to infuse an amount ofmedicament, responsive to the analyte sensor data. In one exemplaryembodiment, the system includes a continuous glucose sensor andprocessor module including a flow profile (e.g., programming) configuredfor infusion of an amount of an insulin solution (e.g., such that acalculated amount of insulin is infused) in response to the host'sglucose concentration. For example, processor module is configured toand/or includes programming that processes the continuous glucose sensordata, whereby the host's glucose level is determined in real time. Inpreferred embodiments, the processor module is configured to calculatethe volume of insulin solution to be infused, such as if the host'sblood glucose exceeds a predetermined threshold (e.g., the host ishyperglycemic; e.g., glucose above 120 mg/dl, 130 mg/dl, 140 mg/dl, 150mg/dl, 160 mg/dl, 170 mg/dl or more), the processor calculates an amountof insulin to be delivered to the host (e.g., an amount of insulinsolution sufficient to lower the host's glucose to or near thepredetermined range). In preferred embodiments, the processor modulere-programs the flow profile to deliver the amount of infusion solutionrequired to deliver the calculated amount of insulin (e.g., a bolusamount), and the flow control device infuses the amount of solutionresponsive to the re-programming of the flow profile. For example, insome embodiments, the processor module is configured to insert (e.g.,add) a medicament infusion phase into the flow profile. As the host'sblood glucose level approaches and/or reaches the predetermined range,the processor module is configured to re-program the flow profile toreduce the amount of insulin-containing solution infused. For example,in some embodiments, the processor module is configured to re-programthe flow profile to infuse a basal level of insulin, such as duringwashing of the sensor.

Pumpless Sample Withdrawal

In some circumstances, it is preferred to meter the flow of a fluidthrough a vascular access device (including withdrawal of at bloodsample) without the use of a pump and/or a flow control device (e.g.,described above). Accordingly, some embodiments provide a system forcontinuously measuring an analyte in an artery of a host in vivo, whichdoes not require the use of the flow control device of the preferredembodiments or of a pump. Accordingly, in some preferred embodiments,the system includes an arterial infusion system and continuous analytesensor coupled thereto. The arterial infusion system is configured andarranged to meter the flow of a fluid into and/or out of an artery of ahost, and includes an arterial catheter, a pressure transducer, aninfusion fluid, and a pressure system. The pressure system is configuredto increase and/or reduce an amount of pressure applied to the infusionfluid, such that when the infusion system is applied to the host (e.g.,the catheter is implanted in the host's artery), the pressure system caninfuse the infusion fluid, withdraw a blood sample, and reinfuse awithdrawn sample into the host. In general, arteries are pressurized.Accordingly, blood will expelled from a puncture in the artery (e.g., aninserted/implanted catheter, a cut or breakage) unless pressure greaterthan the arterial pressure is applied thereto, such as via compression,a pressure cuff, a pressurized infusion system, and the like. Anarterial pressure system can be configured to infuse fluid into the hostby increasing the pressure applied to the infusion fluid, such as (butnot limited to) by increasing the pressure applied with a blood pressurecuff, such that the applied pressure overcomes the arterial pressure. Inpreferred embodiments, the system is configured to withdraw a sample(e.g., contact the sensor with the blood sample) by reducing the appliedpressure (in a controlled manner) until a sample of blood is pushed intothe catheter (by the arterial pressure) and contacts the sensor. In someembodiments, the withdrawn sample is reinfused into the host, such as byincreasing the applied pressure such that the arterial pressure is againovercome and infusion fluid flows into the host. In some embodiments,the withdrawn sample is diverted to waste disposal, such as via a valve.In some embodiments, the system is configured such that the sensingportion of the sensor are disposed within the host's body (e.g., withinthe artery) as described herein. However, in other embodiments, thesensor is disposed extracorporeally (e.g., above a plane defined by thehost's skin) and the sample is withdrawn out of the host's body. Inpreferred embodiments, the system includes electronics configured toregulate the pressure system, such that infusion and sample withdrawalare controlled.

The analyte sensor can be configured to detect a variety of analytes, asdescribed elsewhere herein. In some embodiments, the analyte sensorincludes a single working electrode, which generates a first signalassociated with the concentration of the analyte in the sample. In otherembodiments, the analyte sensor is a dual-electrode continuous analytesensor, as described elsewhere herein, and includes a first workingelectrode configured to generate the first signal (including ananalyte-related signal component and a non-analyte-related signalcomponent) and a second working electrode is configured to generate asecond signal (including the non-analyte related signal component).

In some embodiments, a method for continuously measuring an analyte inan artery of a host in vivo is provided. In this embodiment, the methodincludes the steps of coupling a continuous analyte sensor with anarterial catheter system applied to a host, wherein the sensor isconfigured to generate an analyte-related signal associated with ananalyte in a sample, and wherein the arterial catheter system includesan arterial catheter, a pressure transducer, an infusion fluid, and apressure system configured to increase and/or reduce an amount ofpressure applied to the infusion fluid; reducing the amount of pressure,such that a sample of arterial blood contacts the sensor; and generatingthe analyte-related signal with the sensor. In some embodiments, thecoupling step includes coupling the sensor to the arterial catheter,such as by inserting the sensor into a lumen of the arterial catheter.In some embodiments, the method includes a step of reinfusing the sampleinto the host, such as by increasing the amount of pressure. In someembodiments, the arterial blood pressure of the host is monitored, usingthe pressure transducer. Arterial pressure monitors are known in theart. In preferred embodiments, the analyte-related signal is processedto provide an analyte value. In some embodiments, the signal is alsocalibrated.

In some embodiments, the generating step further includes generating asecond signal with the sensor, wherein sensor includes a first workingelectrode configured to generate a first signal including ananalyte-related signal component and a non-analyte-related signalcomponent and the second working electrode is configured to generate thesecond signal including the non-analyte-related signal component. Thefirst and second signals can be processed, to provide a processed signalsubstantially without a signal component due to the non-analyte-relatedsignal component, and/or to provide a scaling factor. In someembodiments, the generating step further includes generating a referencesignal associated with a reference analyte in the sample, wherein thesensor further includes a reference sensor configured to generate thereference signal.

Systems and Methods for Processing Sensor Data

In general, systems and methods for processing sensor data associatedwith the preferred embodiments and related sensor technologies includeat least three steps: initialization, calibration, and measurement.Although some exemplary analyte sensors, such as glucose sensors, aredescribed in detail herein, the systems and methods for processingsensor data can be implemented with a variety of analyte sensorsutilizing a variety of measurement technologies including enzymatic,chemical, physical, electrochemical, spectrophotometric, polarimetric,calorimetric, radiometric, and the like. Namely, analyte sensors usingany known method, including invasive, minimally invasive, andnon-invasive sensing techniques, configured to produce a data signalindicative of an analyte concentration in a host during exposure of thesensor to a biological sample, can be substituted for the exemplaryanalyte sensor described herein.

In some embodiments, the sensor system is initialized, whereininitialization includes application of the sensor and/or sensor systemin or on the host. In some embodiments, the sensor system includes acomputer system including programming configured for performing one ormore of the following functions: turning the system on, requestingand/or receiving initial data (e.g., time, location, codes, etc),requesting and/or receiving patient data (e.g., age, conditions,medications, insulin dosing, etc), requesting and/or receivingcalibration information (e.g., manufacturer calibration lot data,reference information such as solution(s) provided for calibration,etc.), requesting information related to the flow control device, andthe like.

In some embodiments, the sensor system is configured with apredetermined initial break-in time. In other embodiments, the sensorsystem is configured to determine when break-in is complete (e.g., thesensor signal is substantially stabilized). In some embodiments, thesensor's sensitivity (e.g., sensor signal strength with respect toanalyte concentration) and/or baseline is used to determine thestability of the sensor; for example, amplitude and/or variability ofsensor sensitivity and/or baseline may be evaluated to determine thestability of the sensor signal. In alternative embodiments, detection ofpH levels, oxygen, hypochlorite, interfering species (e.g., ascorbate,urea, and acetaminophen), correlation between sensor and referencevalues (e.g., R-value), and the like may be used to determine thestability of the sensor. In some embodiments, sensor stability isevaluated by determining if and/or when sensor break-in is complete. Insome embodiments, the sensor is configured to calibrate during sensorbreak-in, thereby enabling measurement of the biological sample prior tocompletion of sensor break-in.

In one embodiment, systems and methods are configured to processcalibrated sensor data during sensor break-in. In general, signalsassociated with a calibration and/or measurement phase of the sensorsystem can be measured during initial sensor break-in. Using a ratemethod for measuring an analyte (e.g., measuring the rate of change of astep change), a sensor signal can be calibrated with a correction factorto account for the rate of change of the break-in curve. In oneexemplary embodiment, the bottom of sequential step responses (e.g., ofcalibration phases during sensor break-in) is fit to a line or curve(e.g., using linear or non-linear regression, such as least squaresregression), to extrapolate the rate of change of the curve of thesensor break-in. Accordingly, the rate of change measured in ameasurement phase is corrected to account for the rate of change of thesensor break-in curve, and the sensor signal calibrated. By calibratingduring sensor break-in, sensor data can more quickly be provided (e.g.,to the user interface) after sensor insertion.

In some embodiments, systems and methods are configured to determine aninitial baseline value of the sensor. In general, baseline refers to acomponent of an analyte sensor signal that is not substantially relatedto the analyte concentration. In one example of a glucose sensor, thebaseline is composed substantially of signal contribution due to factorsother than glucose (for example, interfering species,non-reaction-related hydrogen peroxide, or other electroactive specieswith an oxidation/reduction potential that overlaps with hydrogenperoxide).

In preferred embodiments, the sensor system includes a computer systemincluding programming configured to determine calibration informationand calibrate a signal associated with a biological sample there from.In general, calibration of the signal includes initial calibration,update calibration and/or re-calibration of the sensor signal. Althoughsome systems and methods for calibrating a sensor are described in moredetail elsewhere herein, for example in the section entitled, “SensorElectronics,” additional and alternative methods for providingcalibration information and calibrating the sensor's signal are providedin the following description and can be used in combination with and/oralternative to the methods described elsewhere herein.

The term “calibration information” generally refers to any information,such as data from an internal or external source, which provides atleast a portion of the information necessary to calibrate a sensor. Insome embodiments, calibration information includes steady stateinformation, such as baseline information and/or sensitivity informationobtained by processing reference data from an internal and/or externalreference source, which is described in more detail elsewhere herein. Insome embodiments, calibration information includes transientinformation, such as rate of change information and/or impulse responseinformation obtained by processing a signal produced during exposure ofthe sensor to a step change (e.g., sudden or nearly sudden change) inanalyte concentration, which is described in more detail elsewhereherein.

In some embodiments, steady state information includes reference datafrom an external source, such as an analyte sensor other than the sensorof the sensor system configured to continuously measure the biologicalsample, also referred to as external reference data or externalreference value(s). In some embodiments, calibration informationincludes one, two, or more external reference values (e.g., fromself-monitoring blood glucose meters (finger stick meters), YSI GlucoseAnalyzer, Beckman Glucose Analyzer, other continuous glucose sensors,and the like). In some embodiments, one or more external referencevalues are requested and/or required upon initial calibration. In someembodiments, external reference value(s) are requested and/or requiredfor update calibration and/or re-calibration. In some embodiments,external reference values are utilized as calibration information forcalibrating the sensor; additional or alternatively, external referencevalues can be used to confirm the accuracy of the sensor system and/orto detect drifts or shifts in the baseline and/or sensitivity of thesensor.

In one exemplary embodiment, at least one external reference value incombination with at least one internal reference value together providecalibration information useful for calibrating the sensor; for example,sensitivity of a sensor can be determined from an external referencevalue and baseline can be at least partially determined from an internalreference value (e.g., a data signal indicative of an analyteconcentration in a reference solution during exposure of the sensor tothe reference solution, which is described in more detail elsewhereherein).

In another exemplary embodiment, calibration information includes two ormore external reference values that provide calibration informationuseful for calibrating the sensor; for example, at least two SMBG metervalues can be used to draw a calibration line using linear regression,which is described in more detail elsewhere herein.

In yet another exemplary embodiment an external reference value isutilized to confirm calibration information otherwise determined (e.g.,using internal reference values).

In some embodiments, steady state information includes reference dataobtained from the analyte sensor to be calibrated, also referred to asinternal reference data or internal reference values. In one exemplaryembodiment, internal reference data includes a signal associated withexposure of the sensor to one or more reference solutions (e.g.,calibration solutions), which is described in more detail elsewhereherein.

In some embodiments, the sensor system includes one or more referencesolutions (e.g., calibration solutions in some embodiments), wherein thesystem is configured to expose the sensor to the one or more referencesolution(s) to provide calibration information (e.g., an internalreference value), such as baseline and/or sensitivity information forthe sensor. In one exemplary embodiment, a reference solution includinga known analyte concentration is provided, wherein the system isconfigured to expose the sensor to the reference solution, and whereinthe system is configured to produce a data signal indicative of ananalyte concentration in the reference solution during exposure of thesensor to the reference solution, as described in more detail elsewhereherein. In some embodiments, two reference solutions with two differentanalyte concentrations are provided. For example, in order to generatereference values for detecting sensitivity drift of a glucose sensor,two saline solutions containing 100 and 200 mg/dl glucose respectivelycan be provided.

In general the system can be configured to obtain internal referencevalues at one or more time points, intermittently, and/or continuously.For example, in some embodiments, calibration for drift in baselineand/or sensitivity can be done at set time intervals, depending upon theseverity of the drift. In some circumstances, it is preferred tocalibrate very frequently (e.g., between about every 1 minute or lessand about every 2, 3, 4, 5, 10, 15, 20 or 30 minutes or longer). Inother circumstances, it is preferred to calibrate less frequently (e.g.,about every 1, 2, 3, 5, 10, 15 or 24 hours or longer). For example, insome circumstances, baseline drift has a substantial effect on sensoraccuracy, while sensitivity drift has little effect. Accordingly, abaseline calibration solution (e.g., 0-mg/dl glucose) can be used tocalibrate the baseline about every 5 minutes. Thus, to calibrate forsensitivity drift, an analyte-containing calibration solution (e.g.,100-mg/dl glucose in saline) can be used to calibrate the sensor lessfrequently, such as about once every 1, 2, 3, 5, 10, 12, 24, 48 or morehours. In some embodiments, one or more external reference values, suchas reference values obtained by testing a blood sample with SMBG or aYSI device, can be used to calibrate the system, in addition to theinternally provided reference values (e.g., provided via the calibrationsolutions).

Although much of the description focuses on the use of a referencecalibration solution to provide an internal reference value, othersensor technologies, such as optical sensing methods, are known toprovide one or more internal reference standards (e.g., of knownabsorbance, reflectance, fluorescence, etc) to determine baseline and/orsensitivity information, as is appreciated by one skilled in the art;accordingly, the systems and methods described herein can be implementedwith other types of internal reference values. Examples of analytesensors configured for optical detection of the analyte and/or areference analyte are described in detail in the section entitled“Optical Detection,” above. In some embodiments, a “plateau” is reachedwhen the sensor has been exposed to the sample of bodily fluid (e.g.,blood) or a reference solution a sufficiently long period of time thatthe sensor's enzyme has used up (e.g., reacted with, detected)substantially all of the available analyte.

In some embodiments, the sensor system is configured to use a steadystate measurement method, from which steady state information can beobtained. Steady state information can be obtained during exposure ofthe sensor to an analyte concentration when the signal has reached a“plateau” wherein the signal is representative of the analyteconcentration; the term plateau does not limit the signal to a flatsignal, rather the plateau represents a time point or time period duringwhich the signal is substantially stable and a data point thatrepresents the analyte concentration can be reliably obtained.

FIG. 11 is a graph that schematically illustrates a signal producedduring exposure of the sensor to a step change in analyte concentration,in one exemplary embodiment. The x-axis represents time; the y-axisrepresents sensor signal (e.g., in counts). In general, a step changeoccurs when a sensor is sequentially exposed to first and seconddifferent analyte concentrations, wherein the signal (after the changefrom exposure of the sensor to the first analyte concentration toexposure of the sensor to the second analyte concentration) includes ameasurable rate of change (transient information) that subsequently“plateaus” or substantially “plateaus” to a signal that substantiallyrepresents the analyte concentration to which the sensor is exposed(steady state information). As one example, a step change occurs when asensor is exposed to a reference solution of a first analyteconcentration and then subsequently exposed to a reference solution of asecond, different, analyte concentration. As another example, a stepchange occurs when a sensor is exposed to a reference solution of aknown analyte concentration and then subsequently exposed to abiological sample of unknown or uncalibrated analyte concentration.

Referring to FIG. 11, at a first time point 1002, a sensor is exposed toa step change in analyte concentration, for example, from a zeroconcentration reference analyte solution to a biological sample ofunknown or uncalibrated analyte concentration. During the initial signalresponse to the step change, a rate of change 1004 of the signal can bemeasured for a time period. In some embodiments, for example when thestep change is between two known reference solutions, the rate of changeinformation can provide transient information useful for calibrating thesensor, which is described in more detail elsewhere herein. However, ifeither of the first and/or second analyte concentrations of the stepresponse is not known, the rate of change information, alone, cannotprovide sufficient calibration information necessary to calibrate thesensor.

Point 1006 represents a point in time that the signal response shiftsfrom transient information (e.g., rate of change) to steady stateinformation (e.g., plateau), in some embodiments. Namely, the signal,beginning at point 1006, substantially accurately represents the analyteconcentration and can be used in steady state equations to determine ananalyte concentration, in some embodiments. In one exemplary embodimentof steady state equations useful for calibrating the sensor system, thecalibration information is obtained by solving for the equation y=mx+b,wherein: “y” represents the sensor data value (e.g., digitized in“counts”) determined at a single point (or averaged value over a windowof data where signal is indicative of analyte concentration, forexample); “b” represents baseline (e.g., unrelated to the analyte); “m”represents sensitivity (e.g., for a glucose sensor, counts/mg/dL); and“x” is the concentration of the reference solution (e.g., known analyteconcentration in a reference calibration solution (e.g., glucose inmg/dL)). In this exemplary embodiment, steady state information includessensitivity and baseline.

In some embodiments, the sensor data value (v) can be obtained from amoving window that intelligently selects a plateau during exposure ofthe sensor to an analyte concentration. In some embodiments, the sensorsystem is configured to be exposed to two or more known referencecalibration solutions from which steady state information (sensitivityand baseline) can be processed to calibrate the sensor system; namely,by providing two known analyte concentrations, the steady state equationdescribed above can be utilized to solve for baseline and sensitivity ofthe sensor, which can be utilized to define a conversion function orcalibration factor, such as described in more detail elsewhere herein.

Referring again to FIG. 11, point 1006 is a point that can be used as“y” in the steady state equation described above. In some embodiments,the point 1006 is easily determinable as it is the beginning of a signalplateau 1008 (represented by a dashed line); accordingly, the systemincludes programming to process the data signal to determine the signalplateau and/or a time point therein. In general, a step change producesa signal plateau in the signal response, which is indicative of a steadystate response to the analyte concentration measurement. In someembodiments, the system includes programming configured determine thetime period (window) during which the signal has reached a plateau andchoose a single point or average point from that window.

In some situations, however, the point 1006 and/or plateau 1008 may notbe easily determinable. For example, in some sensor systems, thediffusion of certain non-analyte species (e.g., baseline, backgroundand/or interfering species), which may diffuse more slowly than theanalyte (e.g., through a membrane system that covers the analytesensor), do not reach a steady state during the same time period thatthe analyte reaches a steady state. In these situations, the signal maynot “plateau” in a measurable manner because of the reaction of thelagging species through the membrane system, which generate additionalsignal over the actual analyte plateau 1008. In other words, while theanalyte concentration may have reached a plateau, the baseline has not.Dashed line 1010 represents the signal response to a step change in sucha situation, for example, wherein the signal does not substantially“plateau” due to the lagging diffusion of certain non-analyte species,resulting in a non-measurable analyte plateau. In these situations,additional information is required in order to provide calibratedanalyte sensor data. Systems and methods for providing additionalinformation and/or to provide sufficient calibration information tocalibrate an analyte sensor in such situations are described in moredetail below, with reference to conjunctive measurements, for example.

In some embodiments, the sensor system is exposed to a referencesolution with a known analyte concentration of about zero, and whereinthe steady state information comprises baseline information about thesensor in the reference solution. For example, a glucose sensor systemcan be exposed to a 0 mg/dl glucose solution (e.g., an isotonic solutionwithout any glucose concentration) and the signal associated with thezero glucose concentration in the reference solution providescalibration information (steady state) indicative of at least a portionof the baseline of the sensor.

It has been observed that, in some circumstances, the signal associatedwith the zero glucose concentration in a reference solution (such assaline) is not equivalent to the baseline signal when the sensor isexposed to a biological sample (e.g., blood) from which the sensor isconfigured to obtain its analyte concentration measurement; rather thebaseline includes an additional amount of signal associated with thedifferences between the composition of the reference solution and thehost's blood. This additional signal is referred to as “offset” (e.g.,b_(offset), see FIG. 11, 1016 and associated text). Offset is anindication of the level of noise present in the system, the presence ofan interferent in the solution and/or in the blood, and/or the like. Insome circumstances, additional information may be required in order todetermine and/or confirm baseline of a biological sample (e.g., blood).In some embodiments, 1, 2, 3 or more external reference analyte valuesare obtained (e.g., via finger stick, a clinical analysis device (e.g.,YSI) and the like) and entered into the system, such as for use indetermining b_(offset). For example, in some embodiments, the equitationy=mx+(b+b_(offset)) is used to calibrate the sensor, wherein m isdetermined when the sensor is exposed to calibration solution, b isdetermined from the dual-electrode and b_(offset) is an externalreference value, such as but not limited to a finger-stick referencevalue (in counts). In some embodiments, error is substantially mitigatedby evaluating two or more external reference analyte values fordeviation therebetween, such as by averaging them, detecting outliers,and the like. In one embodiment, the external reference analyte value iscompared to an estimated or calculated analyte value, such as to confirmthe accuracy of a calculated b_(offset). For example, in someembodiments, the difference between a finger-stick glucose value (e.g.,in counts) and a calculated blood glucose value (e.g., in counts) isused as the b_(offset) in future calculations. In some embodiments, anoffset threshold is set, based on a priori information (e.g., determinedfrom numerous in vitro and/or in vivo experiments and/or theliterature). For example, in some embodiments, the threshold is basedon, at least in part, the maximum and/or minimum possible offsets for agiven sensor configuration, a give type of host, and/or the like. Insome embodiments, the calibration solution includes additionalcomponents provided to overcome baseline in blood, for example. In someembodiments, a factor is determined (e.g., from historical data) todetermine an adjustment factor for a difference between baseline in thebiological sample (e.g., blood) and baseline in the reference solution.In other embodiments, two calibration solutions are used to evaluateb_(offset). In some embodiments, baselines of the working electrodes isdetermined prospectively, such as by testing in the reference solutionby the manufacturer. In some embodiments, the difference in baseline ofa biological sample (e.g., blood) and the baseline of the referencesolution, also referred to as b_(offset) herein, is determined usingother techniques, such as described in more detail below.

In general, the calibration information described above, including aknown baseline and sensitivity, can be used to determine a conversionfunction or calibration factor applied to convert sensor data (“y”) intoblood glucose data (“x”), as described in more detail elsewhere herein.

In some embodiments, systems and methods are configured to obtaintransient measurement information associated with exposure of the sensorto a reference solution of known analyte concentration and/or abiological fluid of unknown or uncalibrated analyte concentration. Insome embodiments, the system is configured obtain transient informationby exposing the sensor to a step change in analyte concentration andprocess the rate of change of the associated signal. In someembodiments, the system is configured to obtain transient information byexposing the sensor to a step change in analyte concentration andprocessing the impulse response of the associated signal.

In one exemplary embodiment, the sensor is exposed to a first referencesolution of a known analyte concentration and then to a second referencesolution of a known analyte concentration to determine the rate ofchange of the signal response. In these embodiments, the equation(Δy/Δt=r·Δx) can be used to obtain the transient information, wherein“Δx” is the difference between the two known solutions that are beingmeasured (e.g., 0 mg/dL to 100 mg/dL in an exemplary glucose sensor),“Δy” is the measured difference between the sensor data (e.g., incounts) corresponding to the analyte concentration difference in knownreference solutions (Δx), “Δt” is the time between the two “y” sensormeasurements referenced with Δy, and “r” represents the rate of changecalibration factor, or rate of change conversion function, that can beapplied for that particular sensor to obtain calibrated blood glucosemeasurements from sensor rate of change data.

In some embodiments, transient information can be obtained from the rateof change of a signal produced during exposure of the sensor to abiological sample of unknown or uncalibrated analyte concentration. Insome embodiments, transient information can be obtained from the stepand/or impulse response of a signal produced during exposure of thesensor to a step change in analyte concentration.

In some embodiments, neither steady state information, nor transientcalibration measurements are used in isolation in calibrating the sensorsystem, but rather steady state and transient information are combinedto provide calibration information sufficient to calibrate sensor datasuch as described in more detail, below. For example, in someembodiments, wherein baseline is not completely known (e.g., b_(offset)must be determined), wherein a rate of change calibration factor is noteasily determinable (e.g., when multiple known reference solutionscannot be pushed substantially immediately adjacent to each other toprovide a rate of change indicative of the step or impulse response),wherein the a steady state measurement cannot be obtained (e.g., due tolagging species affecting the analyte signal plateau), and the like. Insome embodiments, both steady state information and transientinformation are processed by the system to provide sensor calibration,confirmation, and/or diagnostics. In some embodiments, transient sensorinformation from unknown or uncalibrated blood glucose measurements canbe processed to provide calibration information for the sensor system,such as described in more detail below.

In some embodiments, once at least a portion of the calibrationinformation is determined, the sensor system is configured to expose thesensor to a biological sample and measure a signal response thereto. Insome embodiments, the sensor can be continuously exposed to thebiological sample, wherein at least some external reference values areused as calibration information for calibrating the sensor system. Insome embodiments, the sensor can be intermittently exposed to thebiological sample, wherein at least some internal reference values areused as calibration information for calibrating the sensor system, alsoreferred to as auto-calibration in some exemplary embodiments.

In some embodiments, the sensor system is calibrated solely using steadystate information, such as described in more detail elsewhere herein. Inone such embodiment, the sensor system is configured to be exposed to abiological sample and a value (y) determined from the signal plateau,which is used in combination with a conversion function (calibrationfactor) that uses steady state information (e.g., sensitivity andbaseline) to obtain a calibrated analyte concentration (e.g., glucoseconcentration in mg/dL or mmol/L) equivalent to the measured sensor datavalue y.

In general, the sensor system of the preferred embodiments can beconfigured to utilize any combination the steady state information(e.g., from external and/or internal sources) described in more detailelsewhere herein. In some embodiments, the sensor system includessystems and methods configured to calibrate the sensor based on one,two, or more external reference values. In some embodiments, the sensorsystem includes systems and methods configured to calibrate the sensorbased on one or more external reference values, which calibration can beconfirmed using an internal reference value (e.g., zero analyteconcentration reference solution). In some embodiments, the sensorsystem includes systems and methods configured to calibrate the sensorbased on one external reference value in combination with one internalreference value to determine baseline and sensitivity information. Insome embodiments, the sensor system includes systems and methodsconfigured to calibrate the sensor based on internal reference values,also referred to as auto-calibration. In general, auto-calibrationincludes the use of one or more reference solution to calibrate thesensor system. In some embodiments, the sensor system includes systemsand methods configured to calibrate the sensor based on priorinformation, which is described in more detail elsewhere herein. In someembodiments, the sensor system includes systems and methods configuredto calibrate the sensor based on dual working electrodes, bysubstantially eliminating the baseline component of the steady statecalibration equation (e.g., (y=mx)).

In some embodiments, the sensor system includes systems and methodsconfigured to calibrate the sensor based solely on transient information(e.g., rate of change, decay, impulse response, etc) described in moredetail elsewhere herein. In one exemplary embodiment, analyteconcentration can be determined from the change in sensor dataresponsive to a step change (Δx), the time (Δt) elapsed between thesensor data measurements Δy, and the rate of change calibrationfactor/rate of change conversion function, such as described in moredetail above.

In some embodiments, the sensor system includes systems and methodsconfigured to calibrate the sensor based on conjunctive information,wherein the calibration information used to calibrate the sensor systemincludes both steady state information and transient information.

In one exemplary embodiment, the sensor system includes systems andmethods configured to calibrate the sensor based on a rate of change(transient information) associated with a signal produced duringexposure of the sensor to a step change between a reference solution ofknown analyte concentration (e.g., 0 mg/dl glucose) and a biologicalsample; in this exemplary embodiment, a reference value (steady stateinformation) from an external analyte sensor (e.g., blood glucose meter)can be obtained for the analyte concentration in the biological sample,thereby providing sufficient information to solve for calibration usingrate of change of the signal response to the step change there between.One advantage of using rate of change calibration methods includes itsinsensitivity to baseline and interfering species.

In one preferred embodiment, a system is provided for monitoring analyteconcentration in a biological sample of a host, the system including: asubstantially continuous analyte sensor configured to produce a datasignal indicative of an analyte concentration in a host during exposureof the sensor to a biological sample; a reference solution including aknown analyte concentration, wherein the system is configured to exposethe sensor to the reference solution, and wherein the sensor isconfigured to produce a data signal indicative of an analyteconcentration in the reference solution during exposure of the sensor tothe reference solution; and a computer system including programmingconfigured to determine calibration information and calibrate a signalassociated with a biological sample there from, wherein the calibrationinformation includes steady state information and transient information.In some embodiments, the calibration information is determined from asignal associated with exposure of the sensor to the reference solutionand a signal associated with exposure of the sensor to a biologicalsample.

One situation wherein steady state information and transient informationare useful together for calibrating a sensor system includes a situationwhere a baseline measurement obtained from an internal reference(b_(reference)) provides only a portion of the baseline informationnecessary for calibrating the sensor system. As one example, thebaseline of blood is different from the baseline of saline (e.g.,reference) and compounds or molecules that make up the baseline in bloodcan create artifacts (e.g., b_(offset)), which can make calibrationusing internally derived steady state information alone, difficult.Namely, plateau 1008 (FIG. 11) in the signal responsive to the stepchange in analyte concentration does not occur in blood, in someembodiments, due to slow diffusion of baseline-causingcompounds/molecules to the sensor electroactive surface; instead, anartifact 1010 (FIG. 11) is observed in the signal. Accordingly, in someembodiments, baseline information useful for calibration of a sensorsystem includes both b_(reference) and b_(offset). A variety of systemsand methods of determining b_(offset), which can be useful in providingcalibration information and/or diagnostics and fail-safes, has beendiscovered, as described in more detail elsewhere herein.

In some embodiments, b_(offset) can be determined from transientinformation derived from a signal associated with exposure of the sensorto a biological sample, wherein the biological sample is of unknown oruncalibrated analyte concentration.

In one preferred embodiment, a system for monitoring analyteconcentration in a biological sample of a host is provided, the systemincluding: a substantially continuous analyte sensor configured toproduce a data signal indicative of an analyte concentration in a hostduring exposure of the sensor to a biological sample; a referencesolution including a known analyte concentration, wherein the system isconfigured to expose the sensor to the reference solution, and whereinthe system is configured to produce a data signal indicative of ananalyte concentration in the reference solution during exposure of thesensor to the reference solution; and a computer system includingprogramming configured to determine calibration information andcalibrate a signal associated with a biological sample there from,wherein the calibration information is determined from a signalassociated with exposure of the sensor to the reference solution and asignal associated with exposure of the sensor to a biological sample,wherein the biological sample is of unknown or uncalibrated analyteconcentration.

In some embodiments, systems and methods are configured to process animpulse response of a signal associated with exposure of the sensor to abiological sample, wherein the biological sample is of unknown oruncalibrated analyte concentration, in order to determine an offsetbetween a baseline measurement associated with a reference solution anda baseline measurement associated with a biological sample (e.g.,b_(offset)).

FIG. 12 is a graph that schematically illustrates a derivative of thestep response shown in FIG. 11. FIG. 12 can also be described, as theimpulse response of the signal associated when a sensor is exposed to astep change to a biological sample of unknown or uncalibrated analyteconcentration, in one exemplary embodiment. In this embodiment, theimpulse response can be defined by a sum of two exponentials functions(e.g., (ae^(−k1*t)-ae^(−k2*t)), where k1 and k2 are time constantscharacteristic of the sensor), wherein the impulse response starts at 0at t=0 and is expected to decay to 0 as t becomes large (as timepasses). The impulse response reaches a peak, shown as point 1050 inFIG. 12, which represents the maximum rate of change of the associatedsignal (see FIG. 11, for example). Additionally, although it is expectedthat the signal will decay to 0 as t becomes large, FIG. 12 illustratesa plateau 1052 above the y-axis; namely, wherein the plateau 1052 doesnot hit 0.

It has been discovered that the positive value 1054 of the plateausubstantially represents the slope of the b_(offset) artifact 1010 (FIG.11). Accordingly, when the slope is drawn from t=0 of the step response(see line 1012 of FIG. 11), the “y” value 1016 of that slope line at theend of the step response 1014, represents b_(offset). Accordingly,b_(offset) can then be added to the equation y=mx+b (whereb=b_(reference)+b_(offset)) and a conversion function (calibrationfactor) can be determined to calibrate the sensor system (i.e., usingboth steady state information and transient information and includingusing the signal associated with exposure of the sensor to a biologicalsample of unknown or uncalibrated analyte concentration.)

In some alternative embodiments, systems and methods are configured toprocess an impulse response (such as shown in FIG. 12) associated with astep change (such as shown in FIG. 11) to determine a time point of asteady state measurement during which an analyte concentration can beobtained. As described above, in some circumstances, it can be difficultto determine a steady state time point (e.g., 1006 in FIG. 11) at whichtime point the signal accurately represents the analyte concentration.Accordingly, systems and methods configured to determine the time point(e.g., 1006 in FIG. 11) in the step response associated with exposure ofthe sensor to a biological sample of unknown or uncalibrated analyteconcentration have been discovered, which time point accuratelyrepresents the analyte concentration in the biological sample. Becausethe impulse response can by defined by exponentials (discussed above),systems and methods can be configured to process the exponentialequation (s) with variable parameters to determine a best-fit to theimpulse response curve determined from exposure of the sensor to thebiological sample. It has been discovered that this best fit of theimpulse response provides sufficient information to determine the timepoint 1056 (FIG. 10) at which the decay curve should have decayed to they-intercept; namely, the time point 1056 where the decay curve shouldhave hit y=0 indicates the (steady state) time point in the stepresponse (e.g., 1006 in FIG. 11) that accurately represents the analyteconcentration without the b_(offset) artifact 1010. Accordingly,(y=mx+b) can then be used to calibrate the sensor system, including thesignal value “y” at the time indicated by the extrapolated impulseresponse curve (e.g., and using sensitivity and baseline informationdetermined from one or more reference calibration solutions, such asdescribed in more detail elsewhere herein.

In some other alternative embodiments, systems and methods areconfigured to compare steady state information and transient informationfor a plurality of time-spaced signals associated with biologicalsamples of unknown or uncalibrated analyte concentration to determine anoffset between a baseline measurement associated with a referencesolution and a baseline measurement associated with the biologicalsamples.

In some exemplary embodiments, b_(offset) is determined by plottinglevel (i.e., the point at which the step response plateaus or ends) vs.rate (i.e., maximum rate of change of the step response determined fromthe peak of the impulse response curve) for a plurality of stepresponses (e.g., time-spaced signals) and drawing a regression line ofthe plotted points, such as described in more detail with reference toFIG. 13.

FIG. 13 is a graph that illustrates level vs. rate for a plurality oftime-spaced signals associated with exposure of the sensor to biologicalsamples of unknown or uncalibrated analyte concentration. The y-axisrepresents maximum rate of change for each step response; the x-axisrepresents level (signal level (e.g., in counts) obtained at the plateauof the signal and/or the end of the step response.) Each point 1080 onthe plot represents level vs. rate for each of the plurality oftime-spaced signals. A regression line 1082 is drawn using knownregression methods, as is appreciated by one skilled in the art. Thepoint 1084 at which the line 1082 crosses the y-axis represents thesignal associated with a reference (e.g., 100 mg/dL calibrationsolution) plus b_(offset). Accordingly, b_(offset) can be determined bysubtracting the signal associated with the reference from the point 1084at which the line 1082 crosses the y-axis. Thus, b_(offset) determinedfrom the plot as described above, can be included in the equation y=mx+b(where b=b_(reference)+b_(offset)) and a conversion function(calibration factor) can be determined to calibrate the sensor system(i.e., using both steady state information and transient information andincluding using the signal associated with exposure of the sensor to abiological sample of unknown or uncalibrated analyte concentration.)

In some embodiments, b_(offset) is an adjustable parameter, wherein thesensor system includes systems and methods configured to determineb_(offset) with each measurement cycle (each time the sensor is exposedto the biological sample) and to adjust the calibration factor(conversion function), including b_(offset) with each measurement cycle,responsive to a change in b_(offset) above a predetermined threshold,and/or responsive to external information, for example.

In some embodiments, systems and methods are provided to detect a shiftin the baseline and/or sensitivity of the signal based on a comparisonof steady state information and transient information, such as describedin more detail with reference to FIG. 13. In some embodiments, systemsand methods are provided to correct for a shift in the baseline and/orsensitivity of the signal based on a comparison of steady stateinformation and transient information. In some embodiments, systems andmethods are provided to initiate a calibration responsive to detectionof a shift in the baseline and/or sensitivity of the signal based on acomparison of steady state information and transient information.

Referring again to FIG. 13, regression line 1082 is shown for a selectedplurality of time spaced signals. In some embodiments, multipleregression lines can be drawn for a plurality of different windows oftime spaced signals (e.g., time-shifted windows). In these embodiments,a comparison of a regression line from a first window of time spacedsignals as compared to a regression line drawn from a second window oftime spaced signals can be used to diagnose a shift and/or drift insensor sensitivity and/or baseline. For example, in FIG. 13, line 1082represents a regression line drawn for a first window of data over afirst period of time; dashed line 1086 represents a regression linedrawn for a second window of data over a second period of time; anddashed line 1088 represents a regression line drawn for a third windowof data over a third period of time. In this example, dashed line 1086is shifted along the y-axis from the first line 1082, indicating a driftor shift in the sensor's baseline from the first time period to thesecond time period; dashed line 1088 is shifted along the x-axis fromthe first line 1082, indicating a drift or shift in the sensor'ssensitivity from the first time period to the third time period.Accordingly, a shift in the regression line can be used to diagnose ashift or drift in the sensor's signal and can be used to trigger acorrective action, such as update calibration and/or re-calibrationusing any of the methods described herein. Additionally oralternatively, the shift in the line can be used to correct a shift ordrift in the sensor's signal; for example, the amount of shift in theline can be used to update calibration accordingly (e.g., the change iny-value between two regression lines can be representative of acorresponding change in baseline between two time periods, and thecalibration information updated accordingly). One skilled in the artappreciates that some combination of shift or drift of the baseline andsensitivity can occur in some situations, which can be similarlydetected and/or corrected for.

Sensor Sensitivity Evaluation

In some circumstances, noise on the sensor signal can be mistaken as adrift in sensor sensitivity. It has been empirically determined, throughevaluation of large in vivo and/or in vitro data sets, that sensorsensitivity generally follows an expected pattern of drift, over theperiod of sensor use. For example, in one exemplary sensorconfiguration, during the first hour or so, of sensor use (e.g., afterstart-up and/or re-start-up after a period of disuse), sensitivity tendsto change rapidly; after this period, the sensitivity increase tends tolevel off and/or plateau. However other sensitivity profiles arepossible based on sensor design. While each individual sensor'ssensitivity profile can vary from that of other such sensors, dependingupon factors such as sensor design, membrane chemistry, implantationsite, and the like, it has been found that sensor profiles tend tofollow an empirically determined pattern of drift within a range ofabout ±5%, ±10%, ±15%, ±20% or ±25%. Deviations from the expectedpattern can be indicative of noise on the sensor, sensor failure, and/orthe like, which can be dealt with as described elsewhere herein, such asthe section entitled “Diagnostics and Fail-Safes.”

FIG. 14 is a flow chart illustrating sensor sensitivity evaluation, insome embodiments. In preferred embodiments, systems and methods areconfigured to process a plurality of sensitivity calculations, todetermine if an apparent sensitivity drift falls within the expectedprofile.

At block 1400, a method for evaluating a change in sensitivity of ananalyte sensor over a predetermined time period is provided. In someembodiments, the predetermined time period is relatively short, such asbut not limited to less than or equal to about 30 minutes, also referredto as short-term sensitivity evaluation. In some embodiments, relativelyshorter periods of time, such as 25, 20, 15, 10, 5 minutes arepreferred. For example, in one embodiment, the evaluated sensitivitiesare calculated about every 5 minutes. In other embodiments, thepredetermined time period is longer. For example, in one embodiment, thetime period is at least about 30 minutes, also referred to as long-termsensitivity evaluation. In other embodiments, the predetermined timeperiod is at least about 60 minutes. For example, in some embodiments,the predetermined time period is about 70, 80, 90, 100, 110, 120, 130,140, 150, 160, 170, 180, 190 or 200 minutes, or longer.

At block 1402, sensor data is received from an analyte sensor. Forexample, in some embodiments, the system includes an input module, alsoreferred to as the processor module, configured to receive the sensoranalyte data. The sensor data can include one or more sensor analytevalues measured in a bodily fluid of a host (e.g., blood). In someembodiments, an individual measurement is used. In some embodiments, anaverage of a plurality of time-spaced points is used. In someembodiments, reference analyte values are also received by the inputmodule. For example, in vivo reference analyte values can be generatedwhen the sensor is contacted with a reference solution. In someembodiments, reference analyte values are intermittently received. Forexample, in some embodiments, the in vivo reference analyte values aregenerated when the sensor is intermittently in contact with thereference solution (e.g., calibrant), such as according to the flowprofile (e.g., see FIG. 10E). For example, if the sensor is included inan integrated system, such as depicted in FIG. 6 and as described withreference to FIGS. 10A-10E, wherein the flow control device movesbetween the controlled flow and gravity flow valve positions, such as atflow rates and times specified by the flow profile, and the sensorgenerates sensor data when the sensor is contacted with blood andreference values when the sensor is in contact with the referencesolution. Additionally or alternatively, in some embodiments, thereference analyte value(s) are obtained from an in vitro analyte monitor(e.g., external reference analyte values). For example, a self monitoredblood glucose monitor can be used to obtain external reference glucosevalues (e.g., from a finger-stick blood sample), which can be enteredinto the system, as described elsewhere herein.

At block 1404, analyte sensor sensitivity is calculated intermittently(e.g., periodically or non-periodically), based at least in part on thereference analyte data, such as described elsewhere herein. For example,in some embodiments, the processor module is configured to and/orincludes programming that calculates sensor sensitivity using theformula y=mx+b, wherein m is the sensitivity value (e.g., estimatedand/or measured). For example, in some embodiments, the intermittentlyreceived reference analyte values are used to intermittently calculatethe sensitivity of the analyte sensor, such as but not limited to fromabout once every 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 25 or 30-minutes to about once every 1, 1.5,2, 2.5 or 3-hours or longer. In some embodiments, a plurality ofsensitivities is calculated over a predetermined time period. Forexample, in some embodiments, the processor is configured to and/orincludes programming that calculates 2, 3, 4, 5, 6, 7, 8, 9, 10 or moresensitivities over a pre-programmed time period of 10, 15, 20, 30, 40,50, 60, 70, 80, 90 or 120-minutes or longer. In some embodiments, thesensitivities are calculated iteratively. For example, as the integratedsystem cycles through phases of blood and reference solution measurementaccording to the system's (e.g., the processor module's) flow profile(e.g., programming). In some embodiments, the sensitivity values arefiltered, such that each calculated sensitivity value is a filteredvalue. For example, in some embodiments, the data (e.g., referenceanalyte values) are filtered prior to use in calculation of the sensorsensitivity m (e.g., via an IIR or FIR filter). In another example, insome embodiments, the data (within a window of data) are averaged (e.g.,equally or non-equally weighted average, mean-value, median, or thelike) prior to use in calculation of sensor sensitivity. In yet anotherexample, in some embodiments, two or more calculated sensitivities arefiltered, averaged, smoothed, and/or the like.

At block 1406, a plurality of time-spaced sensitivity calculations areevaluated over a predetermined time period. For example, in someembodiments, the plurality of time-spaced sensor calculations areevaluated to determine whether or not the sensor's sensitivity didchange (e.g., drift), and if so, did the change in calculatedsensitivities follow the empirically determined pattern, was theobserved change due to noise, and the like, as described below. In someembodiments, the processor is configured to calculate a change (e.g.,drift) in sensor sensitivity using the formula

${Drift} = \frac{m_{t\; 1} - m_{t\; 2}}{m_{t\; 1}}$

and/or the formula

${{Drift} = \frac{m_{t\; 1} - m_{t\; 2}}{( {m_{t\; 1} + m_{t\; 2}} )/2}},$

wherein m_(t1) is the calculated sensitivity at time 1, and m_(t2) isthe calculated sensitivity at time 2, for example. In preferredembodiments, this evaluation is performed iteratively on the pluralityof time-spaced sensitivity calculations over the predetermined timeperiod. In some embodiments, at least two sensitivity values areevaluated during the predetermined time period. For example, in someembodiments, the difference between two sensitivity calculations (e.g.,the amount of change) is evaluated. In some embodiments, the at leasttwo sensitivity values are averaged and/or filtered (e.g., smoothed toremove noise) before they are evaluated. Filtering the sensitivitycalculations can provide a smoother trajectory (e.g., curve) forevaluation of sensitivity drift by eliminating outliers and/or randomnoise (e.g., non-specific noise). The sensitivity calculations can befiltered using a variety of methods (e.g., FIR, IIR, averaging) asdescribed elsewhere herein. In other embodiments, all of the sensitivitycalculations over the time period are evaluated. In further embodiments,all sensitivity calculations are evaluated at a plurality of time pointsduring sensor use. For example, a sensor session can last from the timewhen the sensor is implanted and/or the flow control device is turned onto the time when the system is turned off and/or the sensor is removed.In another example, a sensor can be implanted for an extended period oftime, such as three or more days, with intermittent periods of use(e.g., when the power is on and the system is functioning). For example,the system may be intermittently powered down, such as during certainmedical procedures. The period of sensor use before the powering down isconsidered to be a sensor session, in some embodiments. Similarly, theperiod of sensor use after the restart (e.g., power-up, re-power-up) isconsidered to be a sensor session, in some embodiments.

In some embodiments, a change in sensitivity is evaluated by comparingit (the change in sensitivity) with one or more criteria. For example,in some embodiments, a priori sensitivity information is used (at leastin part) to evaluate the change in sensitivity. In general, a prioriinformation includes information, data and/or observations generatedduring many previous in vitro and/or in vivo experiments, as well asinformation, data, and/or observations gleaned from the scientificliterature. In some embodiments, the a priori sensitivity informationincludes and/or provides an expected profile (e.g., an expected patternand/or amount of sensitivity change/drift over time). For example, ithas been observed that in some sensor designs, the sensor sensitivitytends to increase over time, wherein the increase tends to occur withinan expected range. For example, it has been observed that sensorsensitivity tends to increase over time (e.g., no substantial decreaseover time), wherein the increase tends to occur within an expectedrange, wherein the magnitude of the change is related to the length oftime the sensor has been used and/or implanted and/or energized (e.g.,turned on). Deviation from the expected profile can be indicative of afailure of a portion of the integrated system, a detrimental change inthe host's condition, and/or the like, in some embodiments. In someembodiments, the system is configured to evaluate and/or consider adeviation from the expected profile in combination with additionalinformation (e.g., interferents, noise, completion of break-in, etc.) todetermine if a system failure has occurred.

In some embodiments, the a priori sensitivity information defines arange (e.g., within boundaries and/or guard bands) of acceptable change(increase and/or decrease) in sensitivity. For example, in somecircumstances, sensitivity can change (e.g., drift) up to about ±5%,±10%, ±15%, ±20%, ±25%, ±30%, ±40%, ±50%, ±60%, ±70%, ±80%, ±90%, ±100%,±200% or more over a given time period (e.g., over a time period ofabout 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120 minutesor longer). In some embodiments, an acceptable change in sensitivity isrelated to how long the sensor has been in use, implanted and/orenergized.

In some embodiments, a change in sensitivity is evaluated using a “cone”of feasible sensitivity values of the sensor, such that aberrantsensitivity changes (e.g., artifacts) are detected whenever thesensitivity value (e.g., amount of sensitivity change, a calculatedchange in sensitivity over a time period) falls (e.g., occurs) outsideof the cone of possibility. In one embodiment, the cone of possiblesensitivity values is defined in terms of a range of allowable (orfeasible) sensitivity change for a time point during a sensor session.The range of allowable sensitivity change can change over time during asensor session, for example, by allowing a greater sensitivity changeduring an earlier time period of a sensor session than a later timeperiod of a sensor session. In general, sensitivity information dependsupon sensor design and can be obtained from analysis of data sets (e.g.,a priori information). A known feasible range can be represented (e.g.,drawn) on a graph as a “cone of possible sensitivity values” (e.g., arange of possible calculated sensitivity values, for the next timeperiod, based at least in part on one or more previously calculatedsensitivity value(s) and a priori information). In some embodiments, oneor more criteria used to determine the cone of possible sensitivityvalues are defined by an expected profile. For example, the cone ofpossibility initiates at the calculated sensitivity value of a firsttime period (e.g., the point of the cone) and projects forward in time(e.g., becomes broader), such that the broadest portion of the cone(e.g., the “base” of the cone) is located at and/or is projected towardor past the second time period. At the second calculated sensitivityvalue graphed, another “cone of possibility” can be drawn for the nexttime period (e.g., a third time period), wherein this new cone ofpossibility is based on the expected profile, and so on.

Accordingly, in embodiments wherein sensitivity is evaluated in theshort-term (e.g., over periods of 30-minutes or less), when the changein sensitivity meets the one or more criteria (e.g., falls within theboundaries of the expected profile, is within a cone of feasible change,and/or the like), the system is configured to use the most recentsensitivity calculation evaluated (e.g., for sensor calibration and thelike). Similarly, the system is configured to not use a most recentsensitivity calculation evaluated to calibrate the analyte sensor whenthe change in sensitivity does not meet one or more criteria. In somecircumstances, the change in sensitivity not meeting the one or morecriteria can trigger a sensor failure, an alert, an alarm, a fail-safe,and the like, as described elsewhere herein.

In some embodiments, evaluation of sensor sensitivity is conducted usinga dual-electrode continuous analyte sensor. As described elsewhereherein, a dual-electrode analyte sensor includes two working electrodes,which are configured to provide two signals. The first signal includesan analyte component and a baseline component. The second signalincludes a baseline component without an analyte component. As describedelsewhere herein, in some embodiments, sensitivity of a dual-electrodeanalyte sensor is calculated using the signal from either (or both) ofthe working electrodes. Accordingly, in some embodiments, theintermittent sensor sensitivity calculations are based at least in parton the first signal or based at least in part on the second signal. In afurther embodiment, the second signal is subtracted from the firstsignal to obtain a subtracted signal, wherein the step of intermittentlycalculating a sensitivity of the analyte sensor is based at least inpart on a subtracted signal, combined with signals measured by thesensor when exposed to reference solution and/or blood. In someembodiments, a difference in sensitivities of the plus-enzyme andno-enzyme working electrodes is evaluated. For example, with respect toa dual-electrode glucose sensor exposed to a calibration solution (e.g.,a glucose-containing infusion solution) the sensitivity measured by theno-enzyme electrode can be used as the sensitivity value for the enzymeelectrode and/or subtracted signal as described in more detail elsewhereherein.

In some embodiments, sensor sensitivity can be calculated using anexternal reference value generated from a blood sample (e.g., a splitsample, finger-stick), wherein the external reference value is measuredusing another test device, at the bedside or in a clinical laboratory.For example, in the case of glucose sensors, external reference valuescan be generated by a finger-stick or testing a blood sample using anYSI device. Use of external reference values (e.g., baseline valueobtained via finger-stick and/or YSI) in calculation of sensorsensitivity is preferred in some embodiments, such as but not limited tonon-dual-electrode continuous analyte sensors.

In an exemplary embodiment, a method for evaluating a change insensitivity of an analyte sensor over a predetermined time period isprovided, wherein sensor data is received from an analyte sensor,wherein the sensor data includes one or more sensor analyte valuesmeasured in a biological sample of a host, a sensitivity of the analytesensor is intermittently calculated based at least in part on referenceanalyte data, and a change in sensitivity is evaluated by evaluating aplurality of time-spaced sensitivity calculations over a predeterminedtime period. For example, the processor module is configured to and/orincludes programming that evaluates the change in sensitivity of theanalyte sensor over the predetermined time period. In some embodiments,the predetermined time period is less than or equal to about 30, 25, 20,15, 10, or 5 minutes. In other embodiments, the predetermined timeperiod is at least about 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120minutes.

In another exemplary embodiment, a system for evaluating a change insensitivity of an analyte sensor over a predetermined time period isprovided. In this embodiment, the system includes a computer systemincluding an input module configured to receive sensor analyte data andreference analyte data, wherein the sensor data includes one or moresensor analyte values measured in a biological sample of a host andwherein the reference data includes one or more reference analytevalues, and a processor module configured to (1) intermittentlycalculate a sensitivity of the analyte sensor based at least in part onthe reference analyte data and to (2) evaluate a change in sensitivityby evaluating a plurality of time-spaced sensitivity calculations over apredetermined time period. In some embodiments, the predetermined timeperiod is less than or equal to about 30, 25, 20, 15, 10, or 5 minutes.In other embodiments, the predetermined time period is at least about30, 40, 50, 60, 70, 80, 90, 100, 110 or 120 minutes.

In some embodiments, wherein the predetermined time period is less thanor equal to about 30 minutes, also referred to as short term sensitivityevaluation, evaluating a change in sensitivity includes evaluating atleast two sensitivity measurements during the predetermined time period.For example, the processor module is configured to and/or includesprogramming that evaluates at least two sensitivity measurements duringthe predetermined time period, to evaluate the change in sensitivity.For example, in one embodiment, the at least two sensitivitymeasurements are separated by 30 minutes. In other embodiments, the atleast two sensitivity measurements are separated by 25, 20, 15, 10, or 5minutes. In some further embodiments, the processor module is configuredto and/or includes programming that averages and/or filters the at leasttwo sensitivity measurements prior to evaluating the at least twosensitivity measurements. In some circumstances, averaging and/orfiltering the at least two sensitivity measurements can reduce theaffect of outlier data points on the evaluation.

In some embodiments, wherein the predetermined time period is less thanor equal to about 30 minutes, the processor module is configured toand/or includes programming that compares the change in sensitivity withone or more criteria. For example, the one or more criteria include butare not limited to an expected profile of sensitivity change for thetime period and/or a cone of possibility (e.g., a range of allowablesensitivity change), such as described above. In some embodiments, theprocessor module is configured to and/or includes programming that usesa most recent sensitivity calculation evaluated to calibrate the analytesensor when the change in sensitivity meets one or more criteria. Inother embodiments, the processor module is configured to and/or includesprogramming that does not use a most recent sensitivity calculationevaluated to calibrate the analyte sensor when the change in sensitivitydoes not meet one or more criteria.

In some embodiments, wherein the predetermined time period is less thanor equal to about 30 minutes, the step of intermittently calculating asensitivity of the analyte sensor includes intermittently receiving areference analyte value. For example, in some embodiments, the processormodule (also referred to as a receiving module) is configured to and/orincludes programming that intermittently receives the reference analytevalue(s). In some circumstances, reference analyte values can bemeasured by the system. In some embodiments, the system is configured toperiodically receive a measured analyte concentration from a referenceanalyte solution. For example, in some embodiments, the sensor isexposed to the reference analyte solution, such that the sensor measuresthe analyte concentration of the reference analyte solution. In otherembodiments, the reference analyte values are measured outside of thesystem. For example, in some embodiments, a reference analyte valueobtained from an in vitro analyte monitor is received by the system.

In some embodiments, wherein the predetermined time period is less thanor equal to about 30 minutes, the step of evaluating a sensitivity isiteratively performed on the plurality of time-spaced sensitivitycalculations over the predetermined time period. For example, in someembodiments, the processor module is configured to and/or includesprogramming that evaluates a sensitivity calculation every 5, 10, 15,20, 25 or 30 minutes.

In some embodiments, wherein the predetermined time period is at leastabout 30 minutes, also referred to as long term sensitivity evaluation,the processor module is configured to and/or includes programming thatiteratively performs the sensitivity evaluation on the plurality oftime-spaced sensitivity calculations over the predetermined time period(e.g., at least about 30 minutes). In some embodiments, the step ofevaluating a sensitivity includes evaluating all of the sensitivitycalculations over a sensor session. For example, if the sensor sessionis 3-days, then all of the sensitivity calculations from the sensorsession up to the time of sensitivity evaluation are evaluated.Similarly, if the sensor session lasts 4, 5, 6, or 7 days, then all ofthe sensitivity calculations over that period of days are evaluated. Insome embodiments, the processor module is configured to evaluate asensitivity based at least in part on a priori sensitivity information.For example, a priori sensitivity information can be obtained fromprevious sensor uses, such as numerous in vitro and/or in vivoexperiments. In some embodiments, the a priori sensitivity informationincludes an expected profile. For example, during the first hour ofsensor use, the expected profile may be a line having a slope and/orcurvature within a first range; while during the second hour of use theexpected profile may be a line having a slope and/or curvature within asecond range. In some embodiments, the a priori sensitivity informationdefines a range of acceptable change in sensitivity, such as describedwith reference to a cone of possible acceptable and/or feasiblesensitivity changes. For example, a range of acceptable change insensitivity can include changes in sensitivity observed 80%, 85%, 90% or95% of the time, in numerous previously conducted in vitro and/or invivo experiments (e.g., uses), for a given time period of sensor useand/or implantation.

In some embodiments of evaluating a change in sensitivity of an analytesensor over a predetermined time period, the analyte sensor includes twoworking electrodes configured to provide a first signal (e.g., from theplus-enzyme working electrode) including an analyte component and abaseline component and a second signal e.g., from the no-enzyme (e.g.,non-enzymatic) working electrode) including a baseline component withoutan analyte component. In some further embodiments, the processor moduleis configured to and/or includes programming that intermittentlycalculates a sensitivity of the analyte sensor based at least in part onthe first signal. In some further embodiments, the step ofintermittently calculating a sensitivity of the analyte sensor is basedat least in part on the second signal. In some further embodiments, theprocessor module is configured to and/or includes programming thatsubtracts the second signal from the first signal to obtain a subtractedsignal, wherein the step of intermittently calculating a sensitivity ofthe analyte sensor is based at least in part on the subtracted signal.

In some embodiments of evaluating a change in sensitivity of an analytesensor over a predetermined time period, the analyte sensor isintermittently exposed to a biological sample (e.g., blood) and to areference solution (e.g., an infusion solution containing a definedamount of analyte), such as described elsewhere herein. In some furtherembodiments, the processor module is configured to and/or includesprogramming that intermittently calculates a sensitivity of the analytesensor based at least in part on a signal obtained when the analytesensor is exposed to a biological sample (e.g., when blood is drawn backby the flow control device, according to the flow profile). In somefurther embodiments, the processor module is configured to and/orincludes programming that intermittently calculates a sensitivity of theanalyte sensor based at least in part on a signal obtained when theanalyte sensor is exposed to a reference solution (e.g., when the flowcontrol device infuses the reference solution, according to the flowprofile). In some further embodiments, the processor module isconfigured to and/or includes programming that intermittently calculatesa sensitivity of the analyte sensor based at least in part on a signalobtained when the analyte sensor is exposed a biological sample and asignal obtained when the analyte sensor is exposed a reference solution.For example, in some embodiments, a subtracted signal, which is derivedfrom the signals obtained when the analyte sensor is exposed to thebiological sample and the reference solution, is used for calculation ofsensor sensitivity.

Sensor Stability Evaluation

It is known that many continuous analyte sensors, such as but notlimited to intravascular sensors, have an initial period of sensor useafter which the sensor signal becomes more stable and substantiallyrepresentative of the analyte concentration (e.g. where the currentoutput from the sensor is stable relative to the analyte level). Thisperiod of time is referred to as “break-in” or “run in.” Sensor break-inis a two-part process, including electrochemical break-in of theelectrodes (e.g., electroactive surfaces) and membrane break-in (e.g.,equilibration with the local environment post implantation). In general,break-in is associated with an exponential signal decay related tobreak-in of the electroactive surfaces. It has been observed that insome sensor system configurations, in addition to the exponential signaldecay, the non-enzyme working electrode signal response to bloodexposure is unstable for at least the first few cycles of systemoperation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cycles),depending upon the flow profile and/or sensor configuration. In thesecircumstances, to effectively remove baseline, in a dual-electrodesensor, it is preferred that the error of the plus-enzyme and no-enzymeworking electrodes be within about ±10% of each other. However, theadditional instability observed on the no-enzyme working electrode, inthese circumstances, tends to increase the difference between the errors(of the two working electrodes), which causes inaccuracies (e.g.,errors) in signal processing (e.g., subtraction of the no-enzyme signalfrom the plus-enzyme signal). While not wishing to be bound by theory,it is believed that the non-enzyme electrode instability is caused, atleast in part, by the affects of biological noise and/or interferents onsome membrane systems. After break-in is complete, these problems withthe no-enzyme signal response are generally no longer observed.

It has been observed that break-in is not a permanent phenomenon. Forexample, it has been observed that when an implanted (e.g., in use)sensor is turned off (e.g., de-energized), after a time, the signaltends to begin destabilizing. In some circumstances, sensor sensitivity(m) begins to deteriorate. For example, calculated sensitivity values(m) may no longer meet the criteria requirements of a sensitivityevaluation (e.g., fall within the cone of possibility). Further, thelonger the sensor remains turned off, the less representative of theanalyte concentration the signal can become. However, the sensor canbreak-in again, if it is re-energized (e.g., turned on again). Thelength of this next break-in period depends, at least in part, on howlong the sensor was turned off. For example, if the sensor was turnedoff for only 10 to 20 minutes, the break-in period could be about 5-10minutes. In another example, if the sensor was turned off for threehours, a full hour or longer may be necessary for the break-in processto be completed. Since it is preferred to use a stable analyte sensorwhen measuring a host's analyte levels, systems and methods fordetermining when the sensor (e.g., the signal) is stable are provided insome embodiments.

Accordingly, in preferred embodiments, the system is configured andarranged to evaluate sensor stability (e.g., determine when and/or ifsensor break-in is complete). Advantageously, evaluation of sensorstability enables improved selection of sensitivity evaluationparameters, and thus improved sensor calibration. For example, in someembodiments, when the sensor is still breaking in, a wider set ofsensitivity (e.g., drift) parameters are selected (e.g., to allowgreater amounts of drift, such as ±30%, ±40%, ±50%, ±60%, ±70%, ±80%,±90%, ±100%, ±200% or more sensitivity drift over a given time period(e.g., 30-min, 1-hr, 2-hrs)). Then, when the sensor signal hasstabilized, a more narrow set of sensitivity parameters are selected(e.g., ±5%, ±10%, ±15%, ±20% sensitivity drift over about 5, 10 or 15minutes). In yet another embodiment, when the sensor is still breakingin (e.g., unstable), the baseline can be determined by means other thansubtraction of the no-enzyme signal from the plus-enzyme signal, such asbut not limited to use of a priori information (e.g., in vitro and/or invivo) and/or external reference analyte values, as described elsewhereherein. In a further embodiment, the system is configured to prompt theuser to enter an external reference value (e.g., a finger-stick) about,near, at and/or after completion of break-in. In some embodiments, thesystem is configured to intermittently (e.g., 1, 2, 3, 4, 5, 6, 7, ormore times every 10, 20, 30, 40, 50 or 60-minute or more) evaluatesensor stability, and to request an external reference value if thesensor has not yet sufficiently stabilized (e.g., if break-in is not yetcomplete). An average break-in time can be empirically determined (e.g.,a priori information). In some embodiments, the system is configured towait a period of time associated with a predetermined break-in time, andto begin evaluating sensor stability after that time period has passed.

FIG. 15 is a flow chart illustrating sensor stability evaluation, in oneembodiment. At block 1500, a method for determining a stability of ananalyte sensor is provided, in one embodiment.

At block 1502, sensor data is received from an analyte sensor, such asby a data receiving module (also referred to as the processor module)operably connected to the analyte sensor system and configured toreceive the sensor data from the sensor. In preferred embodiments, thesensor is a dual-electrode sensor as described elsewhere herein. Forexample, the analyte sensor includes (1) a first working electrode(plus-enzyme electrode) configured to provide first sensor data (e.g., afirst signal), which includes an analyte component and a baselinecomponent, and (2) a second working electrode (no-enzyme electrode)configured to provide second sensor data (e.g., a second signal), whichincludes a baseline component without an analyte component. In someembodiments, the processor module is configured to and/or includesprogramming that uses first sensor data and/or second sensor data, whenthe dual-electrode sensor is exposed to a blood sample, to evaluatesensor stability. In some embodiments, the processor module isconfigured to and/or includes programming that uses the first sensordata and/or the second sensor data, when the dual-electrode sensor isexposed to an infusion solution, to evaluate sensor stability. In someembodiments, the processor module is configured to and/or includesprogramming that uses subtracted signals to evaluate sensor stability.In some embodiments, the processor module is configured to and/orincludes programming that uses only the second sensor data, receivedwhen the sensor is exposed to blood and/or reference solution, in orderto determine when membrane break-in (e.g., membrane stabilizationbetween two working electrodes) is complete.

At block 1504, a stability of the analyte sensor is determined, based atleast in part on the second sensor data (e.g., data from the non-enzymeworking electrode), such as via the processor module. In someembodiments, the processor module is configured to and/or includesprogramming that determines sensor stability by evaluating a change inan amplitude of a plurality of time spaced points (e.g., 2, 3, 4, 5, 10,15, 20, 30, 40, 50 or 100 or more points) from the second sensor data,such as when the sensor is exposed to a sample and/or an infusionsolution. The time space points are spaced by about 1, 3, 5, 10, 15, 20or 30 minutes to about 1, 1.5 or 2-hours or more, in some embodiments.For example, in one embodiment, the processor module is configured tocompare the peak amplitudes from a plurality of measurement phases, suchas when the sensor is exposed to blood. In one exemplary embodiment, theprocessor is configured to and/or includes programming that compares theamplitude (e.g., peak) of a first measurement (e.g., blood) phase to theamplitude of a second measurement phase (e.g., the next measurementcycle). In another exemplary embodiment, the processor is configured toand/or includes programming that compares the amplitude of a firstcalibration (e.g., exposed to calibration or reference infusionsolution) phase to the amplitude of a second calibration phase. Inanother exemplary embodiment, the processor is configured to compare adifference between the amplitudes of the calibration and measurementsphases of a first cycle (e.g., of a flow profile) to a differencebetween the amplitudes of the calibration and measurement phases of asecond cycle. In yet another exemplary embodiment, the processor isconfigured to use the subtracted amplitudes (e.g., the plus-enzymesignal minus the no-enzyme signal). In other embodiments, the processormodule is configured to and/or includes programming that compares afirst point to a second point, wherein the first point is measured whenthe analyte sensor is exposed to the biological sample and the secondpoint is measured when the analyte sensor is exposed to the infusionsolution (e.g., a calibration, wash and/or infusion phase). In otherembodiments, the processor module is configured to and/or includesprogramming that utilizes transient information, such as described withreference to a step-change and FIG. 11, to evaluate the sensor'sstability.

In some embodiments, the processor module is configured to and/orincludes programming that evaluates sensor stability using rate ofchange (ROC) information, such as but not limited to a difference inROCs between two measurement and/or calibration phases of the second(no-enzyme) signal. In some embodiments, the two measurement phases areconsecutive (e.g., obtained during consecutive cycles of the flowprofile). However, in other embodiments, the measurement phases areseparated by one or more measurement and/or calibration phases (e.g.,cycles of the flow profile) and/or spaced in time. For example, in someembodiments, the cycles (e.g., during which the two measurement phasesor two calibration phases occur) are separated by 1, 2, 3, 4, 5, 6, 7 ormore (intervening) cycles; or the cycles (or phases) are separated by 5,10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120 minutes orlonger. In some embodiments, the processor module is configured to waita period of time, such as but not limited to a predetermined break-intime period (e.g., a period of time approximately the length of anaverage break-in time for a particular sensor configuration), prior toevaluating sensor stability. In a preferred embodiment, the processormodule is configured to evaluate a plurality of ROCs, such as but notlimited to a series of 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more ROCs. Forexample, in one embodiment, the processor module is configured evaluatea first ROC (e.g., calculated for first and second measurement phases)and a second ROC (e.g., calculate between second and third measurementphases), relative to a threshold, and so on. In some embodiments, theprocessor module is configured to evaluate a plurality of ROCs within awindow (e.g., moving or non-moving) of calibration or measurementphases, relative to a threshold.

In one exemplary embodiment, the processor module is configured toand/or includes programming that evaluates sensor stability (e.g.,membrane break-in) using a moving predetermined time period (e.g., amoving window) of ROCs calculated from the second signal (e.g., from theno-enzyme electrode). In some embodiments, the moving window encompasses2, 3, 4, 5 or more calculated ROCs. In some embodiments, the processormodule is configured to compare each calculated ROC and/or a differencebetween two ROCs to a threshold, and to assign the ROC a flag (e.g., +1,−1 or 0; categorized as pass/fail, etc.), based on the comparison. Forexample, during the first hour of sensor use, the expected ROC is aboutfrom ±30%, ±40% or ±50% per every 5, 10, 15 or 20 minutes to about ±60%,±70%, ±80%, ±90%, ±100%, ±200% or more per every 5, 10, 15 or 20minutes; whereas, during the second hour of sensor use, the expected ROCis from about ±5% or less every 5, 10, 15 or 20 minutes to about ±10%,±15%, ±20% or ±25% more every 5, 10, 15 or 20 minutes. Accordingly, ifthe ROC exceeds the threshold, it is flagged as +1. If the ROC fallsbelow the threshold, then it is flagged as −1. If, on the other hand,the ROC is within the threshold, then it is flagged as zero (0). In someembodiments, the processor module is configured to determine that thesensor is substantially stable (e.g., break-in is complete) when the sumof the flags is zero. For example, if the pre-determined time period(e.g., a window) encompasses five (5) ROCs, the sum of the 5 flagswithin the window should equal zero, for the sensor to be consideredstable. Preferably, the window is a moving window. For example, in someembodiments, the processor is configured to slide the window forward oneROC with each new cycle. In alternative embodiments, the processormodule is configured such that the sum of the flags within the movingwindow must equal zero at least two times before the sensor isdetermined to be substantially stable. In still other embodiments, theprocessor is configured to evaluate the flags, wherein the value of aplurality of sequential flags (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or moreflags) must equal zero before the sensor is declared to be substantiallystable. In some embodiments, the threshold is associated with theexpected profile. In some other embodiments, the processor module isconfigured to evaluate the first signal (e.g., the plus-enzyme signal)when a sensor (dual-electrode or non-dual electrode) is exposed tocalibration solution, when determining sensor stability. However, inother embodiments, the system is configured to evaluate sensor stabilityusing data received when the sensor is exposed to blood. For example, insome embodiments of a dual-electrode sensor, the processor module isconfigured to calculate the second signal ROCs for two or moremeasurement cycles when the sensor is exposed to blood.

In some embodiments, the sensor is considered to be stable when itreaches a predetermined level (e.g., threshold) of stability (e.g., thesignal is stable and/or substantially representative of the analyteconcentration). Preferably, the processor module is configured to and/orincludes programming that determines a predetermined (e.g., programmed)level of stability has been reached, when an amplitude change of thesecond sensor data meets one or more criteria. For example, in someembodiments, the one or more criteria are designed (e.g., selected) todetect a predetermined threshold (e.g., range) of plateau of the secondsensor data (see FIG. 11 for examples of plateaus (e.g., 1008 and/or1010)). In some embodiments, the expected range of plateaus is based atleast in part on a priori information. Accordingly, in some embodiments,the processor module is configured to determine that the sensor isstable when a plateau of measured second sensor data (e.g., the testdata or waveform) is within the expected range, such as but not limitedto within about ±5%, ±10%, ±15% or ±20% of the expected range. Inaddition to a moving window, sensor stability can be evaluated usingother statistical techniques, such as but not limited to point-to-pointcomparisons, evaluating a measured profile relative to an expectedprofile using covariance, standard deviation, or r-value, and the like.

In preferred embodiments, the system is configured to and/or includesprogramming that provides an output, such as via an output module, alsoreferred to as a processor module, in response to the determination ofthe sensor's level of stability relative to a predetermined threshold.For example, in some embodiments, the processor module is configured toand/or includes programming that displays (e.g., via the user interface)an analyte value, information associated with sensor stability and/orother information on a local and/or remote display of the user interfacein response to a determination of a sensor's stability meeting athreshold (e.g., does the sensor stability meet the threshold or not).In one exemplary embodiment, the processor module is configured toand/or includes programming that displays a first message when thesensor meets the threshold of stability, and a second message when thesensor does not meet the threshold. In another exemplary embodiment, theprocessor module is configured to and/or includes programming thatselects from a menu of messages, symbols, or other indications,responsive to the level of sensor stability determination. For example,in some embodiments, the output includes an indication of at least oneof a numeric estimated analyte value, a directional trend of analyteconcentration, and a graphical representation of a plurality ofestimated analyte values. For example, the output can indicate a requestfor reference analyte data. For example, if the sensor is a glucosesensor, the system can request a finger-stick or YSI reference analytevalue. In another example, the system can request an injection (e.g.,into the tubing) of a defined amount of analyte, such that the systemcan take a reference measurement as the injected analyte contacts thesensor. In some circumstances, other instructions are provided to thecaretaker, in response to the determination of the predetermined levelof stability. For example, an alert and/or alarm is sounded, such as byvisual and/or auditory components of the user interface.

As described above, the break-in process can occur at various timesduring sensor use, such as during and/or after start-up and afterperiods of disuse. Accordingly, in preferred embodiments, the processormodule is configured to and/or includes programming that determinesstability of the analyte sensor at system start-up and/or after exposureof the sensor to blood and/or a calibration, reference, or infusionsolution. In some embodiments, the processor module is configured toand/or includes programming that determines (e.g., evaluates) stabilityof the analyte sensor after a predetermined time period. For example, itis known that, depending upon the sensor's configuration, break-in cantake from about 10, 20, 30 or 40 minutes to about 60, 90, 120 or 180minutes or longer. For a given type of sensor, the average break-in time(e.g., time period, length of time) can be determined mathematicallyusing a priori information. Accordingly, in some embodiments, the systemis configured to begin determining the sensor stability after apredetermined time period (e.g., about half, two-thirds, three-quartersor the entire average break-in period, for that sensor configuration,has passed). In one exemplary embodiment, an exemplary intravasculardual-electrode glucose sensor can take about 1-hour to break-in. In thisembodiment, the system is configured to begin determining (e.g.,evaluating) sensor stability at about 30, 40, 50 or 60-minutes orlonger. In a similar embodiment, analyte sensor stability is determinedafter a system re-start, such as but not limited to in circumstanceswhen the sensor has been turned off for a period of time. For example,the sensor may be turned off when moving the patient, and thenre-started; thus, the sensor's stability is determined when the sensorsystem is re-started.

In one exemplary embodiment, the analyte sensor is a glucose sensor,such as but not limited to a substantially continuous glucose sensordescribed herein (see FIGS. 1A-1J, 2G-3I for exemplary sensorconfigurations). For example, in some embodiments, the sensor is acomponent of the integrated system depicted in FIG. 6, in someembodiments. Preferably, the system (e.g., the processor module is)configured to and/or includes programming that determines the glucosesensor's stability. For example, the system is configured to begindetermining the glucose sensor's stability after about 30, 40, 50, 60 or70 minutes of implantation. In some embodiments, the glucose sensor is adual-electrode continuous glucose sensor, such as a sensor configuredfor implantation into a peripheral vein of the host, wherein thesensor's stability is determined using a plurality of time-spaced sensordata points received from the enzymatic working electrode and/or thenon-enzymatic working electrode, such as but not limited to when thesensor is exposed to blood samples (e.g., during a measurement phase ofthe flow profile) and/or a calibration phase. Determining the glucosesensor's stability can include evaluating the sensor's stabilityrelative to one or more predetermined criteria, such as but not limitedto a profile range (e.g., within about ±5%, ±10%, ±15% or ±20% of anaverage profile) generally observed for that particular type of glucosesensor. In preferred embodiments, the glucose sensor system isconfigured to determine the sensor's stability iteratively and/orperiodically. In a further embodiment, the glucose sensor system isconfigured to determine the sensor's stability after re-start, such asafter a period of disuse, as described herein.

Diagnostics and Fail-Safes

In some embodiments, the system includes programming configured todiagnose a condition of at least one of the sensor and the hostresponsive to calibration information. In some embodiments, the systemintermittently or continuously determines at least some calibrationinformation (e.g., sensitivity information, b_(offset), and the like),each time the sensor is exposed to a reference solution and/or abiological sample.

In one embodiment, systems and methods are configured to find a plateauand/or stable window of data in response to exposure of the sensor to atleast one of a reference solution and a biological sample. In someembodiments, if the system cannot find the plateau and/or stable windowof data, the system is configured to “fail-safe;” for example, in somecircumstances, a lack of plateau and/or stable window of data may beindicative of dilution and/or mixture of the reference solution (e.g.,calibration solution) with the biological sample (e.g., blood), and/orinterruption/disruption of expected/desired fluid flow. Additionally, insome circumstances, a lack of plateau and/or stable window of data maybe indicative of interfering species in the signal.

In general, the term “fail-safe” includes modifying the system (e.g.,the processor module) processing and/or display of data in some mannerresponsive to a detected error, or unexpected condition, and therebyavoids reporting and/or processing of potentially inaccurate orclinically irrelevant analyte values.

In another embodiment, systems and methods are configured to process asignal responsive to exposure of the signal to a reference and/orbiological sample to determine whether the signal is within apredetermined range; if the signal falls outside the range, the systemis configured to fail-safe.

In some embodiments, systems and methods are configured to determinecalibration information including sensitivity information, wherein thesystem includes programming configured to diagnose an error responsiveto a change in sensitivity above a predetermined amount. For example, ina sensor system as described in more detail with reference to theexemplary embodiment of FIGS. 8A to 8C, the system can be configured todetermine a sensitivity value during each calibration phase; and whereinthe system can be configured to fail-safe when the sensitivity of acalibration phase differs from the previously stored sensitivity by morethan a predetermined threshold. In this exemplary embodiment, fail-safecan include not using the sensitivity information to update calibration,for example. While not wishing to be bound by theory, the predeterminedthreshold described above allows for drift in the sensitivity of thesensor, but prevents large fluctuations in the sensitivity values, whichmay be caused by noise and/or other errors in the system.

In some embodiments, systems (including programming) and methods areconfigured to diagnose error in the sensor system by ensuring the sensorsignal (e.g., raw signal of the reference solution(s)) is within apredetermined range. In some embodiments, the sensor signal must bewithin a predetermined range of raw values (e.g., counts, current, etc).In some embodiments, one or more boundary lines can be set for aregression line drawn from the calibration phase. For example,subsequent to performing regression, the resulting slope and/or baselineare tested to determine whether they fall within a predeterminedacceptable threshold (boundaries). These predetermined acceptableboundaries can be obtained from in vivo or in vitro tests (e.g., by aretrospective analysis of sensor sensitivities and/or baselinescollected from a set of sensors/patients, assuming that the set isrepresentative of future data). U.S. Patent Publication No.US-2007-0197889-A1, which is incorporated herein by reference in itsentirety, describes systems and methods for drawing boundaries lines. Insome embodiments, different boundaries can be set for differentreference solutions.

In some embodiments, systems and methods are configured for performingdiagnostics of the sensor system (e.g., continuously or intermittently)during exposure of the sensor to a biological sample, also referred toas the measurement phase, for example, such as described in more detailabove with reference to FIGS. 8A to 8C. In some embodiments, diagnosticsincludes determination and/or analysis of b_(offset). In someembodiments, systems and methods are provided for comparing sequentialb_(offset) values for sequential measurement phases. In someembodiments, the system includes programming configured to diagnose anerror and fail-safe responsive to a change in the b_(offset) above apredetermined amount. In some embodiments, the system includesprogramming configured to re-calibrate the sensor responsive to changesin the b_(offset) above a predetermined amount. In some embodiments, thesystem includes programming configured to detect an interfering speciesresponsive to a change in the b_(offset) above a predetermined amount.

In some embodiments, the system includes programming configured todiagnose a condition of the host's metabolic processes responsive to achange in b_(offset) above a predetermined amount. In some embodiments,the system includes programming configured to display or transmit amessage associated with the host's condition responsive to diagnosingthe condition. While not wishing to be bound by theory, it is believedthat changes in b_(offset) can be the result of an increase (ordecrease) in metabolic by-products (electroactive species), which may bea result of wounding, inflammation, or even more serious complicationsin the host; accordingly, changes in b_(offset) can be useful indiagnosing changes in the host's health condition.

In some embodiments, the system includes programming configured todetect sensor error, noise on the sensor signal, failure of the sensor,changes in baseline, and the like, responsive to a change in b_(offset)above a predetermined amount.

In some embodiments, the system includes programming configured todetermine a time constant of the sensor. One method for calculating atime constant for a sensor includes determining an impulse response to astep change, wherein time at the peak of the impulse response representsa time constant for the sensor. While not wishing to be bound by theory,it is believed that the time constant determined from the peak of theimpulse response should remain substantially the same throughout thelife of the sensor. However, if a shift in the time constant (betweenstep changes and their associated impulse response curves) above apredetermined range is detected, it can be indicative of an unexpectedsensor condition or error, for example. Accordingly, by comparing timeconstants from a plurality of impulse response curves (derived from aplurality of step responses), programming can be configured to diagnosea sensor condition or error and initiate programming (e.g., fail-safe),accordingly.

Accordingly, the system can “fail-safe,” including performing one ormore of the following fail-safe responses: temporarily or permanentlysuspending (e.g., discontinuing) display of analyte data, updatingcalibration or re-calibrating the sensor, requesting external referencevalues, using external reference value(s) as confirmation of a detectedcondition, using external reference value(s) to update calibration orre-calibrate the sensor, shutting the system down, processing the sensordata to compensate for the change in b_(offset), transmitting one ormore messages to the user interface or other external source regardingthe sensor condition, and the like.

In preferred embodiments, the sensor electronics include a fail-safemodule that is configured to detect a system malfunction. The fail-safemodule can be configured to detect a variety of system malfunctions. Forexample, the fail-safe module can be configured to detect electricalmalfunctions, malfunctions of the system fluidics, malfunctions of thesensor, and/or the like. For example, the system electronics can beconfigured to test and/or track the functions of different systemcomponents, and to intelligently recognize aberrant changed in suchfunctions as possible malfunctions.

In some embodiments, the fail-safe module is configured to detectelectrical malfunctions, such as but not limited to short circuit andelectrical malfunction associated with start-up and/or sensor break-in.For example, it is known that an I/R drop across an electrochemicalsensor's working electrode(s) generally occurs during use. The I/R dropcan be monitored for changes, which can be indicative of an electricalmalfunction. Similarly, during use of an analyte sensor in anintravascular system, wherein the sensor is periodically/alternatelyexposed to at least one reference solution and a blood sample, thegenerated signal is expected to rise and fall in a regular fashion, forexample a recognizable wave-form pattern including peaks and valleys.For example, when the enzyme sensor is exposed to blood, the rate of thestep-response indicates the change in glucose from calibration solutionto blood. The plateau of the response also indicates the glucoseconcentration (although the plateau generally indicates the absoluteglucose concentration, not the change in glucose concentration).Accordingly, the fail-safe module can be configured to monitor thepattern of step-responses (e.g., over time) for substantialchanges/deviations, which can be indicative of electrical malfunctions.For example, in some circumstances, the signal can “rail” or “zero,”wherein the signal rapidly changes to a non-physiological analyte valueand remains relatively stable at that non-physiological value for aperiod of time. In some circumstances, the rapid change in value occursat a rate that is also not physiologically possible. In somecircumstances, a comparison of the rate-response (e.g.,transient/kinetic information) versus plateau response (e.g., steadystate information) of each blood measurement can be used as an indicatorof sensitivity drift. Similarly, in some embodiments, comparison ofrate-response versus plateau response on a non-enzymaticelectrode/sensor when expose to blood can provide information related tothe sensor's response to non-glucose species in the sample, which can beused to determine if and/or when to fail-safe.

In some embodiments, the fail-safe module is configured to detectfluidics malfunctions, which can include a malfunction of any part ofthe system configured to contact and/or move a fluid. For example, thevascular access device (catheter) can become occluded, such as due toblood clotting or pressing the in vivo orifice (e.g., catheter tip)against a vessel wall such that fluid cannot move in an out of thevascular access device. In some circumstances, the tubing can becomekinked, the host can move his or her arm such that the catheter becomesbent, bubbles may get into the system, and/or the flow control systemcan malfunction (e.g., not metering fluid flow into the host or notwithdrawing blood samples as it was programmed to do), such thatwashing, calibration, sample collection and the like are not performedas programmed. For example, the sample can become diluted withcalibration solution, there may be clotting on a portion of the sensor,and the like. In one exemplary embodiment, the fail-safe module isconfigured detect fluidics malfunctions by monitoring the pattern ofsignal increases/decreases generated on the working electrode(s), todetect periods of time during which the signal does not follow anexpected waveform (e.g., using known waveform analysis methods and/orpattern recognition algorithms), such as when the signal hits upperand/or lower limits. For example, if the signal zeros for a period oftime, the fluidics system may be unable to withdraw a blood sample dueto kinking of the tubing or occlusion of the catheter. In anotherexample, the signal on the working electrode(s) may stop going back downwhen the tested blood sample should be re-infused into the host and thesensor should be contacted with wash/reference solution, which isindicative of a malfunction of expelling the used sample, washing thesensor, and the like. For example, if the catheter becomes occluded by ablood clot, the flow control system will be unable to meter fluidthrough the catheter.

In some embodiments, the fail-safe module is also configured to detectmalfunctions of the analyte sensor. For example, a sensor malfunctionincludes but is not limited to noise on the signal, drift of sensorsensitivity and/or baseline, a broken component of the sensor, bloodclotting on a portion of the sensor, and cross-talk, as described inmore detail elsewhere herein.

In preferred embodiments, the fail-safe module is further to evaluate adetected malfunction against a criterion. One or more criteria can bepreprogrammed (including reprogrammed) into the system, such as be ahost, a caretaker of the host, and/or the manufacturer. For example, insome embodiments, one or more criteria could be selected from amenu/list of criteria, or manually programmed into the system. Availablecriteria can be responsive to the different types of malfunctions canoccur and/or a user-perceived level of severity and/or urgency.

After a system malfunction has been detected, the fail-safe module isconfigured to provide an alert, an alarm and/or an instruction, such asto the host and/or a caretaker of the host. For example, the system canbe configured to provide an auditory alarm (e.g., beeps, busses, siren,pre-recorded voice message, etc.), a visual alert (e.g., blinking orflashing lights or display screen), a tactile alert (e.g., vibrating),transmitting alerts/instructions to a remote location, such as a nurse'sstation or a doctor's phone/PDA, and the like.

As a non-limiting example, a method is provided for detecting systemmalfunctions via the processing of the data of a continuous analytesensor implanted in a host's circulatory system. As described elsewhereherein, the continuous analyte sensor is configured to generate a signalassociated with an in vivo analyte concentration when the sensor isimplanted in the host. Additionally, the sensor electronics includes afail-safe module configured to detect a system malfunction. Accordingly,the method includes exposing the sensor to a sample from the host'scirculatory system and detecting a malfunction of the system, such asbut not limited to an electrical malfunction, a fluidics malfunction,and/or a sensor malfunction. In some embodiments, an equilibriumanalysis and/or a kinetic analysis of received data/signal is performed.As described elsewhere herein, the data include steady state (e.g.,sensitivity and/or baseline information) and/or transient stateinformation, which can be evaluated/analyzed to provide alerts, alarmsand/or instructions.

As described herein, the system (e.g., the processor module and/orfail-safe module) can be configured to analyze steady state and ortransient state information generated during the step-up response of thesensor, such as during the switch from blood to reference solution andvice versa, also referred to as waveform analysis (for example, usingpattern recognition algorithms, and the like). For example, by analyzingthe step-up waveform of a dual-electrode sensors non-enzymatic workingelectrode, the quality of blood sample aspiration can be evaluated(e.g., fluidics). Similarly, by analyzing the step-down waveform of thesensor's non-enzymatic working electrode, the quality of washing can beevaluated (e.g., fluidics). As another example, analysis of direction ofthe step-up response of the plus-enzyme working electrode upon exposureto blood can used to evaluate calibration accuracy.

System Diagnostics

During operation of the integrated system, wherein the system includes acontinuous analyte sensor implanted in the host's circulatory system anda flow control device (e.g., FIG. 6-7), system artifacts, such as butnot limited to distortion of calibration and analyte measurementwaveforms can occur unexpectedly, for a variety of reasons. For example,anything that affects IV tubing can cause a fluidics malfunction, suchas the host leaning on the IV tubing, or a blood clot fouling the sensoror occluding the catheter and/or vessel. To some extent, sensorcalibration and analyte concentration determination are dependent uponthe quality of the calibration and measurement waveforms, respectively.For example, a good quality waveform can be an indicator that the sensorcan be accurately calibrated with the data comprised in that waveformand/or in a substantially time-corresponding waveform. However, it hasbeen observed that in some circumstances, a signal waveform will be ofpoor quality (e.g., not representative of the system's function), andthe data contained in that waveform is likely to be unsuitable forsubsequent calculations, processes, and the like. For example, a poorquality the waveform can be an indicator that analyte measurements maynot be accurate. Such a circumstance could be detrimental to the host'shealth. In such circumstances, not using (e.g., “throwing out” ordisregarding) the poor quality signal waveform and its associated data,for calculating an analyte concentration, maintains sensor accuracy andsaves time. Accordingly, preferred embodiments provide systems andmethods for performing system diagnostics on the analyte sensor system,for example, such that the quality of a waveform is evaluated prior touse of data comprised in the waveform for sensor calibration and/ordetermination of analyte calibration.

FIG. 16 is a flow chart illustrating system diagnostics, in oneembodiment. At block 1600, a method for performing a diagnostic of ananalyte sensor system is provided, wherein the method includes providinga sensor system, which includes an analyte sensor and a flow controldevice configured to intermittently expose the analyte sensor to abiological sample and to an infusion solution, wherein the analytesensor includes (1) a first working electrode configured to provide afirst signal (e.g., plus-enzyme working electrode) including an analytecomponent and a baseline component and (2) a second working electrodeconfigured to provide a second signal (e.g., second sensor data)including a baseline component substantially without an analytecomponent (e.g., no-enzyme working electrode), and evaluating the sensorsystem based at least in part on the second signal. Suitabledual-electrode continuous analyte sensor systems, such as thoseincluding twisted or bundled working electrodes or with workingelectrodes located within the fluid coupler, are described in detailelsewhere herein, such as but not limited to the sections entitled“Dual-Electrode Analyte Sensors,” “Multi-Sensor Apparatus,” and “SensorConfigurations for Equivalent Measurement of Noise Signals at the TwoWorking Electrodes.” However, other dual electrode analyte sensors canbe used, such as but not limited to those described in U.S. Pat. No.6,175,752 and U.S. Patent Publication No. US-2008-0119703-A1, U.S.Patent Publication No. US-2008-0108942-A1, and U.S. Patent PublicationNo. US-2008-0200789-A1, each of which is incorporated herein byreference in its entirety.

In preferred embodiments, the processor module is configured to and/orincludes programming that evaluates the second signal (e.g., theno-enzyme signal) for an expected shape and/or pattern when the sensoris exposed to a biological sample and/or to an infusion solution. Forexample, in some circumstances, this is done to determine if the systemfluidics (e.g., draw-back and infusion) are functioning properly. Insome embodiments, the system is configured such that the flow profileincludes a measurement phase and an infusion phase. During themeasurement phases, the flow control device is configured to draw-back asample, such that the sample contacts the sensor. It has been observedthat during a measurement phase, the second signal (e.g., no-enzymeworking electrode) waveform tends to rise in a monotonic manner, if thedraw-back was successful. It has also been observed (e.g., over numerousin vitro and in vivo experiments) that during infusion (e.g.,re-infusion of the drawn-back sample, infusion of calibration, acalibration period/phase), the second signal waveform tends to fall(e.g., decline) in a monotonic manner, if the infusion was successful.Deviation from these observed patterns may indicate that the draw-backor infusion was not successful, and, therefore, data comprised in thewaveform may be unsuitable for use in some calculations.

In one exemplary embodiment, the processor module is configured toand/or includes programming that evaluates the second signal todetermine a success of drawing back a biological sample from a host'scirculatory system to the sensor (e.g., to contact the sensor). Forexample, in some embodiments, the system is configured to use datacontained in the measurement waveform to calculate the analyteconcentration, if it (the system, processor module) determines that thedraw-back was successful. On the other hand, the system is configured todisregard/not use data comprised in the measured waveform for subsequentcalculations (e.g., analyte concentration, sensor calibration, etc.), ifit is determined that the draw-back was unsuccessful. In a furtherembodiment, the system is configured to display an analyte valuemeasured during the biological sample draw-back in response todetermining that the draw-back of sample was successful. In anotherexemplary embodiment, the system is configured to evaluate the signal todetermine if an infusion was successful. In some embodiments, asuccessful infusion includes at least one of re-infusing the biologicalsample into the host, washing the sensor (e.g., removing a sufficientamount of sample such that substantially accurate data can be obtainedduring the next sample draw-back without interference from componentsfrom the current sample draw-back) and infusing an amount of infusionsolution. For example, in some embodiments, determining a successfulinfusion includes displaying an analyte value measured in a biologicalsample after the infusing the infusion solution in response to adetermination of a successful infusion.

At block 1602, the analyte sensor is intermittently exposed to abiological sample and to an infusion solution. For example, the flowprofile can include analyte measurement and calibration phases, suchthat the flow control device intermittently draws back blood samplesthat contact the sensor and infuses at least one reference solution, asdescribed elsewhere herein.

At block 1604, the system receives a first signal (e.g., the signal fromthe first working (e.g., plus-enzyme, enzymatic) electrode) includinganalyte and baseline (e.g., non-analyte-related) components and a secondsignal (e.g., the signal from the second working electrode (e.g., thenon-enzymatic, no-enzyme electrode) including a baseline componentwithout an analyte component. As is understood in the art, the signalincludes a waveform, which is referred to as the “signal waveform”and/or the “test waveform.” For example, when the signal (e.g., incounts) is plotted against time, the graph looks like a wave. Thewaveform is associated with the intermittent (e.g., alternating,cyclical) exposure of the sensor to blood and infusion solution. Theiterative (e.g., cyclical, periodic) intermittent exposure of the sensorto blood and infusion solution can generate a plurality of waveforms. Ifthe signal waveform is generated during a calibration phase of the flowprofile (e.g., during exposure of the sensor to a calibration solution),also referred to herein as a “calibration signal waveform,” then atleast a portion of the data generated can be used for calibrating thesensor. If the signal waveform is generated during a measurement phase(e.g., during exposure of the sensor to a sample of the host's blood),also referred to herein as a “measurement signal waveform,” then atleast a portion of the data generated can be used for determining thehost's blood analyte concentration.

At block 1606, the processor module is configured to and/or includesprogramming that evaluates the system, based at least in part on thesecond signal (e.g., the no-enzyme signal of the non-enzymatic (e.g.,second) working electrode). Since the signal generated by the no-enzymeworking electrode includes baseline but substantially no analyte signalcomponent, the shape (e.g., pattern) of the signal waveform generated isassociated with (e.g., diagnostic of) the quality of the system'sfunction (e.g., how well the system is functioning). For example,fluidics and sensor function problems are reflected in the waveform as adeviation from an expected pattern, such as but not limited to anaverage waveform generally observed when a system is in use.

The signal waveform can be evaluated using a variety of methods. In someembodiments, the processor module is configured to and/or includesprogramming that evaluates the signal waveform (e.g., of the secondsignal) by evaluating the signal waveform for an expected shape and/orpattern when the sensor is exposed to a biological sample and/or to theinfusion solution (e.g., a hydration, reference, and/or calibrationsolution). For example, it has been observed, through numerous in vitroand in vivo experiments, that the second signal waveform tends, in acharacteristic way, to rise (e.g., increase) when the sensor is exposedto sample (e.g., blood) and to fall (e.g., decrease) when the sensor isexposed to an infusion solution. In some embodiments, the processormodule evaluates the signal waveform by evaluating a similarity and/orcorrelation between the signal waveform and a waveform template. In afurther embodiment, a second signal waveform is compared to thisexpected shape (e.g., pattern), such as by visual inspection or similarmeans. For example, the second signal waveform and the expected waveformpattern can be graphed together, and then observed and/or evaluated todetermine if they have a similar shape, if they are close together, ifthey substantially overlap (e.g., overlap by about 80%, 85%, 90%, or95%), and the like. In one exemplary embodiment, the system isconfigured to use at least some of the data from the second signalwaveform in subsequent mathematical processes and/or calculations (e.g.,sensor calibration, analyte concentration calculation) if the secondsignal waveform is substantially similar to the expected shape (e.g.,pattern; the signal waveform is of sufficiently and/or substantiallyhigh quality). In a further embodiment, the system is configured to useat least some of the first signal waveform data (e.g., plus-enzymeelectrode) for determining the analyte concentration, calculating sensorsensitivity, calibrating the sensor, and/or the like, when the secondsignal waveform is substantially similar to an expected shape (e.g.,pattern) and/or meets one or more criteria (e.g., falls within athreshold). If the second signal waveform is not sufficiently and/orsubstantially similar to the expected shape (e.g., pattern) and/or doesnot meet the one or more criteria (e.g., it is of lower quality), thenthe system is configured to disregard (e.g., not use, throw out) thesecond signal waveform data for other purposes, such as subsequentcalculations. In a further embodiment, the system is configured todisregard the first signal waveform data (e.g., plus-enzyme electrode)when the second signal waveform is not substantially similar to theexpected shape (e.g., pattern) and/or exceeds the threshold.

In preferred embodiments, the processor module is configured to and/orincludes programming that uses mathematical methods to evaluate a signalwaveform. In some embodiments, one or more waveforms are evaluated usingcorrelation waveform analysis (e.g., cross-correlation). Preferably,correlation waveform analysis quantifies a correlation and/or similarityof corresponding points (e.g., of a measured waveform vs. a waveformtemplate) for a variance, which provides an indication or measurementassociated with directional correlation of the points. Additionally oralternatively, waveform analysis can include systems and methods forquantifying overlap of the corresponding points, namely, an amplitude oramount of difference between the measured waveform vs. a waveformtemplate. In some preferred embodiments, waveform analysis ensuresnormalization of data such that maximum and minimum amplitudes areequivalent for comparison purposes. In general, any of the waveformanalysis described herein can be performed on actual waveforms (signal)or transforms of the waveform, as is appreciated by one skilled in theart.

In some embodiments, a level of quality of the signal waveform isevaluated (e.g., a level of reliability). In some further embodiments,the system is configured to perform one or more tasks, such ascalibrating the sensor, displaying information, or the like, responsiveto the level of quality of the signal waveform, such as describedherein. In some embodiments, the level of reliability is classified aspass or fail, good versus bad, acceptable versus not acceptable. In somefurther embodiments, the system is configured to perform a task when thewaveform is classified as pass, acceptable or the like, such asdescribed herein. In some further embodiments, the system is configuredto perform another task or do nothing when the waveform is notclassified as pass, acceptable, or the like (e.g., the waveform isclassified as failed, not acceptable, etc.).

In some embodiments, when the second signal waveform is compared to anexpected shape (e.g., pattern), a similarity and/or correlation of thesecond signal waveform to a waveform template (e.g., seed template) isevaluated. In some embodiments, the waveform template is based at leastin part on a priori information. For example, a waveform template (for ameasurement or a calibration phase) is generated (e.g., created,calculated, provided, determined, and/or formed) by integrating aplurality of previously generated second signal waveforms. Preferably, awaveform template is generated from a plurality of second signalwaveforms obtained during previous in vitro and/or in vivo experiments(e.g., system uses). While in some embodiments, about 2, 5, 10, 20, 30,40 or 50 second signal waveforms to about 60, 70, 80, 90 or 100 secondsignal waveforms are integrated to generate (e.g., produce, form) thewaveform template, in other embodiments, hundreds or thousands of secondsignal waveforms are integrated to generate a waveform template (e.g.,seed template). In some embodiments, a waveform template is generatedfrom previous sensor sessions from an individual host, such as toprovide an adaptive waveform template.

In some embodiments, the waveform template contains information specificto the sensor system in use, in addition to a priori information. Forexample, in some embodiments, the waveform template is based at least inpart on a second signal waveform measured by the system (e.g., thesystem in use). Preferably, the processor module is configured to and/orincludes programming that updates the template waveform (e.g., with thesecond signal waveform) when a similarity and/or correlation between the(second) signal waveform and the waveform template meets one or morecriteria (and/or fall within a threshold). For example, if the secondsignal waveform substantially correlates with (e.g., at least about 80%,85%, 90% or 95%) the (current) waveform template, the signal waveform isused to update the waveform template, to generate an updated waveformtemplate (e.g., newest, latest version of, most recently updated), alsoreferred to herein as an “adaptive template.” Conversely, if the secondsignal waveform does not meet the one or more criteria, the system isconfigured to not integrate the second signal waveform with the waveformtemplate (e.g., the system can “throw out” the poor quality or badwaveform). In some embodiments, a similarity of the second signalwaveform to the template is evaluated by plotting the second signalwaveform (e.g., the waveform just measured) with the waveform template,wherein the processor module is configured to and/or includesprogramming that determines a correlation (or deviation) of the twowaveforms in shape and/or amplitude. In other embodiments, the secondsignal waveform is mathematically correlated with the template waveform,to determine how they correlate (or deviate). While not wishing to bebound by theory, it is believed that an adaptive waveform templateprovides system diagnostics adapted for each host and use of the system.It should be noted herein that an initial waveform template is used whenthe sensor system is started up, with subsequent use of the adaptivetemplate thereafter. Accordingly, in some embodiments, an adaptivetemplate is substituted for a waveform template as soon as the adaptivetemplate is generated.

In some embodiments, the processor module is configured to and/orincludes programming that detects a level of interferent in thebiological sample (e.g., such as described elsewhere herein). In someembodiments, the waveform template is updated when the level ofinterferent meets one or more criteria. For example, in someembodiments, the processor module is configured to update the waveformtemplate when substantially no interferent (e.g., less than about 20%,10%, 5%, 4%, 3%, 2% or 1% of the signal) is detected. In thisembodiment, if interference is detected on the signal (e.g., above 1, 2,3, 4, or 5% of the signal), then the signal waveform is not used toupdate the template. If, however, interference is not detected on thesignal (or is less than or equal to about 5%, 4%, 3%, 2% or 1% of thesignal), then the processor module updates the waveform template (or theadaptive template) with signal waveform. In some embodiments, a lowerlevel of interferent on the signal, such as 15%, 10%, 5%, 4%, 3%, 2% or1% or less of the signal is acceptable. Accordingly, if the level ofinterferent detected is less than or equal to the criteria (e.g., withinthe threshold) then the waveform template (or the adaptive template) isupdated with the signal waveform. If the level of interferent does notmeet the criteria (e.g., exceeds the threshold) then the waveformtemplate (or adaptive template) is not updated.

In some embodiments, evaluating the sensor system includes detecting aninterferent by evaluating an amplitude, a change in amplitude, thesignal waveform and/or a change in the signal waveform (e.g., of thesecond signal) when the sensor is exposed to the biological sample. Insome embodiments, interferent detection is further based at least inpart on a calibrated analyte value. In one exemplary embodiment, thesystem is configured to look for a change in analyte concentration(e.g., amplitude) above a threshold (e.g., exceeding a criterion) incombination with evaluating a second signal waveform.

In preferred embodiments, the processor module is configured to and/orincludes programming that controls a display of the sensor system basedat least in part on a level of interferent detected. For example, insome embodiments, the processor module is configured to not display ananalyte value measured in a biological sample in response to an amount(e.g., level) of interferent detected on the second signal based on oneor more criteria. For example, when the detected interferent on theno-enzyme working electrode exceeds a predetermined threshold (e.g., anamount of the signal, such as but not limited to 5, 10, 15, 20, or 25%or more of the signal), the analyte value is not displayed. In anexemplary embodiment, what is displayed is responsive to the level ofinterferent detected. For example, if the level does not meet thecriteria, then a first indication (e.g., message or value) is displayed;if the level meets the criteria, then a second indication is displayed;if the level exceeds the criteria, then a third indication is displayed.In another example, if the level of interferent detected meets a firstcriteria, then an indication or message associated with the firstcriteria is displayed; if the level of interferent detected meets asecond criteria, then an indication or message associated with thesecond criteria is displayed; and the like.

In some embodiments, processor module is further configured to processthe first signal and the second signal to obtain a subtracted signal,wherein the step of processing is based at least in part on the level ofinterferent on the sensor system. For example, in some circumstances,the signal is processed to remove offset of the baseline and/orcompensate for a measured interferent (e.g., one or more interferingspecies) on the signal, and/or the like, such as described elsewhereherein.

In a further embodiment, the processor module is configured to fail-safewhen the no-enzyme signal and the analyte concentration (or change inanalyte concentration) do not meet one or more criteria.

As described above, the waveform of the non-enzyme working electrode(e.g., the second signal) has a characteristic pattern. In someembodiments, a characteristic pattern includes monotonicity orsubstantial monotonicity. The term “monotonicity” as used herein is abroad term, and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refers without limitation to aquality of a sequence or function, wherein it is either substantiallyincreasing or substantially decreasing in value, such as but not limitedto about 80%, 85%, 90%, 95% or more of the time. Thus, a measurementsignal waveform generally smoothly rises, while a calibration signalwaveform generally falls smoothly. Accordingly, in some embodiments, thestep of evaluating the sensor system includes evaluating a monotonicityof the signal waveform (e.g., is the signal waveform monotonic or doesis contain bump, jumps, blips, etc.). In some embodiments, the system isconfigured to evaluate the monotonicity of the signal waveform byperforming cross-correlation of the signal waveform with a waveformtemplate. If the signal waveform is not monotonic, is will not correlatewell with the waveform template. In other embodiments, the monotonicityof the signal waveform is evaluated by performing a time-seriesanalysis, or the like.

In some embodiments, the processor module is configured to and/orincludes programming that evaluates a reliability of the system. Forexample, in some embodiments, the signal waveforms generated over aperiod of time (e.g., a window), such as 5, 10, 15, 20 or 30 minutes orlonger, are evaluated, such as to ensure that the waveforms aresubstantially consistent over that period of time. In some embodiments,the window of waveforms to be evaluated is a moving window, encompassingthe 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20 or 30 (or more) most recentlygenerated second signal waveforms.

In some embodiments, evaluating the reliability of the system includesdetermining a level of reliability of the sensor system, such as bycomparing an amplitude, a change in amplitude, a signal waveform and/ora change in a signal waveform of the second signal to one or morecriteria. In some embodiments, the one or more criteria include anexpected waveform shape and/or pattern. For example, if the secondsignal waveforms within a window are substantially monotonic, within apredetermined range of correlation, then the system is configureddetermine a level of reliability (e.g., reliable or “pass”). Conversely,if the second signal waveforms within a window are outside thepredetermined range of monotonicity and/or correlation, the system isconfigured determine a reduced level of reliability (e.g., not reliableor “fail”). A level of 100% reliability of the sensor system can bedefined using known methods, including time-series analysis, standarddeviation, variance, covariance, and/or the like. Accordingly, in someembodiments, the level of reliability of the sensor system is 60%, 65%,70%, 75%, 80%, 85%, 90% or 95% or more as compared to a 100% level asdefined by the methods described above, for example. Depending upon thesystem configuration, various levels of reliability may be acceptable.For example, a low level of reliability may be acceptable for a firstsystem configuration while only a high level of reliability may beacceptable for a second system configuration. Furthermore, in someembodiments, the system is configured to perform one or more functionsor tasks, such as but not limited to calculating a value, displayinginformation, updating a template, and the like, depending upon the levelof reliability, wherein the acceptability of the reliability isassociated with the system configuration.

In other embodiments, evaluating the reliability of the system includesclassifying a signal waveform, such as by comparing an amplitude, achange in amplitude, a signal waveform and/or a change in a signalwaveform of the second signal to one or more criteria. For example, asignal waveform can be classified as “pass” or “fail,” if it meets theone or more criteria. For example, in some embodiments, the system isconfigured to pass the signal waveform when it correlates with thetemplate waveform by at least 50, 55, 56, 70, 75, 80, 85, 90 or 95%. Thesystem can be configured to classify a signal waveform as “pass” or“fail” using other mathematical methods, described elsewhere herein. Insome embodiments, the system is configured to use at least some of thedata in the signal waveform (e.g., second signal) and/or data in atime-corresponding signal waveform (e.g., first signal) for subsequentmathematical processes, such as calibrating the sensor, calculating theanalyte value and the like, when the signal waveform is classified(e.g., declared) as “pass,” such as described herein. Conversely, insome embodiments, the system is configured to not use the data when thesignal waveform is classified as “fail.”

In some embodiments, the system is further configured to control adisplay of the sensor system based at least in part on the level ofreliability of the sensor system (e.g., pass or fail). For example, ifthe system is determined to be reliable, then an analyte value isdisplayed to the user. If, on the other hand, the level of reliabilitydoes not meet one or more criteria, then the system is configured torespond in another way, such as not displaying an analyte value,sounding an alert or alarm, requesting input of information by the user,and the like. In a further embodiment, the system is configured tomodify a subtraction of the second signal from the first signal (e.g.,processing associated with the subtraction) based at least in part onthe reliability of the sensor system.

In some embodiments, the system is configured to evaluate a portion of asecond signal waveform, rather than the entire waveform. For example, ithave been observed that, in some circumstances, an initial portion of asecond signal waveform (e.g., the first eighth, fifth, third, quarter,half, two thirds, three quarters, etc.) may be somewhat unstable, whilethe portion of the second signal waveform from which data is used insubsequent calculations is substantially stabilized. While not wishingto be bound by theory, it is believed that the initial instability ofthe second signal waveform observed is caused by minute variations inthe function of fluidics system (e.g., mechanical movement of the flowcontrol device), membrane effects caused by switching from an infusionsolution to blood (and/or back again, e.g., a step-change), fluiddynamics (e.g., turbulence) and the like that may not affect thereliability of the data. Accordingly, in some embodiments, the system isconfigured to disregard at least some of the initial portion of thesecond signal waveform, when performing system diagnostics, such as butnot limited to evaluating the system (e.g., system fluidics, systemreliability and/or the like).

In some embodiments, the processor module is configured to and/orincludes programming that evaluates the sensor system based at least inpart on the second signal by determining a success of a biologicalsample draw-back from a host's circulatory system to the sensor. Asuccess can be determined and/or quantified by a level of reliability.For example, in some embodiments, the system is configured to determinethat a drawback or infusion was successful if the reliability is atleast 50%. Some embodiments may require a higher level of reliability todetermine that the drawback or infusion was successful. For example, insome embodiments, the system is configured to determine that thedrawback or infusion was successful when the reliability is at least 55,60, 65, 70, 75, 80, 85, 90, or 95% or greater.

In some further embodiments, the system is configured to display ananalyte value measured during the biological sample draw-back inresponse to a determination of a successful biological sample draw-back.For example, success of a draw-back (e.g., the level of reliabilitymeets one or more criteria, or the draw-back is classified as pass) isan indication that the analyte sensor is sufficiently contacted by thesample such that an accurate measurement can be made. Thus, thedisplayed analyte value is not substantially affected by fluidicsproblems and can therefore be considered reliable. In some embodiments,the system is configured to not display the analyte value measuredduring the biological sample draw-back, when the draw-back is determinedto be unsuccessful, such as when the reliability does not meet the oneor more criteria and/or is classified as fail.

In some embodiments, the processor module is configured to and/orincludes programming that evaluates the sensor system based at least inpart on the second signal by determining a success of infusing theinfusion solution such that a biological sample is washed from thesensor. As discussed elsewhere herein, the accuracy of sensormeasurement can be affected by the presence of blood components, fromthe previously drawn back sample, on the sensor. For example, in somecircumstances, red blood cells from a previous drawback might affect thecurrent measurement and cause an inaccurate measurement to be made. Insome embodiments, this problem can be prevented and/or avoided bysufficiently washing the sensor, such as by reinfusing a drawn-backblood sample and infusing one or more amounts of infusion solution atone or more rates, such as according to a flow profile. Thus, in someembodiments, the system is configured such that the sensor is washed ofthe biological sample when the success of the infusion meets one or morecriteria. For example, in some embodiments, the level of success ofinfusion is determined and/or quantified by a level of reliability, suchas described above. In other embodiments, the infusion is classified assuccessful (e.g., pass) or not successful (e.g., fail). In someembodiments, the system is configured to display an analyte valuemeasured in a biological sample after the infusing the infusion solutionin response to a determination of a successful infusion. Accordingly, ifthe infusion was successful, the system displays the analyte value; butif the infusion was not successful, the system does not display theanalyte value.

As a non-limiting example, wherein the system is configured to use a 100mg/dl glucose reference solution and the plus-enzyme working electrodeis exposed to blood having a glucose concentration greater than 100mg/dL, the signal response should step up. When the plus-GOX workingelectrode is exposed to blood having a glucose concentration less than100 mg/dL, the signal response should step down. If the systemcalculated a glucose value less than 100 mg/dL (e.g. 70 mg/dL) when theplus-GOX working electrode stepped up, a calibration error is detectedand the system can fail-safe. Similarly, if the system calculated aglucose value greater than 100 mg/dL (140 mg/dL) when the plus-GOXworking electrode stepped down, an error is detected and the system canfail-safe.

Signal Amplitude and/or Noise Amplitude Analysis and Fail-Safes

In some embodiments, the system is configured to fail-safe when analysisof signal amplitude and/or noise amplitude (residual) of the sensor'sworking electrode(s) indicates that the integrity of the system'selectrical connections are compromised, such as at the sensor or at oneor more components of the system's electronics. For example, in the caseof a dual-electrode sensor, an accuracy and/or reliability of therelationship of the plus-enzyme signal to the non-enzymatic signal isevaluated by comparing signal amplitudes in calibration solution (or inblood). For example, the non-enzymatic signal being greater than theplus-enzyme signal is indicative of a sensor malfunction, and the systemcan fail-safe.

In some embodiments, sensor diagnostics evaluates whether the calculatedsensitivity falls within a predetermined limit and/or range, forexample, 1-10 pA/mg/dL, as described in more detail elsewhere herein. Insome embodiments, the sensor diagnostics evaluates a difference insignal (raw, filtered and/or calibrated) between the non-enzymaticworking electrode and the enzymatic working electrode (e.g., inreference/calibration solution) to determine whether they fall withinpredetermined limits and/or ranges. As one example, a sensor/calibrationdiagnostic evaluates the baseline of the enzymatic and non-enzymaticelectrodes to determine whether they fall within a predeterminedlimit/range.

In some embodiments, the system is configured to use a prioriinformation to set tolerances for sensitivity and/or baseline drift.Preferably, the system is configured to discriminate between measuredchanges in sensitivity and/or baseline from signal artifacts, such as byusing tolerance limits based on historical/empirical data. For example,in some embodiments, if the sensitivity and/or baseline drifts outsidepredetermined limits and the drift is not a transient artifact (e.g., itpersists for a predetermined time period), an error can be detected insensor function and/or calibration.

In yet another alternative embodiment of signal artifacts detection thatutilizes examination or evaluation of the signal information content,filtered (e.g., smoothed) data is compared to raw data (e.g., in sensorelectronics or in receiver electronics). In one such embodiment, asignal residual is calculated as the difference between the filtereddata and the raw data. For example, at one time point (or one timeperiod that is represented by a single raw value and single filteredvalue), the filtered data can be measured at 50,000 counts and the rawdata can be measured at 55,500 counts, which would result in a signalresidual of 5,500 counts. In some embodiments, a threshold can be set(e.g., 5000 counts) that represents a first level of noise (e.g., signalartifact) in the data signal, when the residual exceeds that level.Similarly, a second threshold can be set (e.g., 8,000 counts) thatrepresents a second level of noise in the data signal. Additionalthresholds and/or noise classifications can be defined as is appreciatedby one skilled in the art. Consequently, signal filtering, processing,and/or displaying decisions can be executed based on these conditions(e.g., the predetermined levels of noise).

Although the above-described example illustrates one method fordetermining a level of noise, or signal artifact(s), based on acomparison of raw vs. filtered data for a time point (or single valuesrepresentative of a time period), a variety of alternative methods arecontemplated. In an alternative exemplary embodiment for determiningnoise, signal artifacts are evaluated for noise episodes lasting acertain period of time. For example, the processor (in the sensor orreceiver) can be configured to look for a certain number of signalresiduals above a predetermined threshold (representing noise timepoints or noisy time periods) for a predetermined period of time (e.g.,a few minutes to a few hours or more).

In one exemplary embodiment, a processor is configured to determine asignal residual by subtracting the filtered signal from the raw signalfor a predetermined time period. It is noted that the filtered signalcan be filtered by any known smoothing algorithm such as describedherein, for example a 3-point moving average-type filter. It is furthernoted that the raw signal can include an average value, e.g., whereinthe value is integrated over a predetermined time period (such as5-minutes). Furthermore, it is noted that the predetermined time periodcan be a time point or representative data for a time period (e.g., 5minutes). In some embodiments, wherein a noise episode for apredetermined time period is being evaluated, a differential can beobtained by comparing a signal residual with a previous signal residual(e.g., a residual at time (t)=0 as compared to a residual at (t)−5minutes.) Similar to the thresholds described above with regard to thesignal residual, one or more thresholds can be set for thedifferentials, whereby one or more differentials above one of thepredetermined differential thresholds defines a particular noise level.It has been shown in certain circumstances that a differentialmeasurement as compared to a residual measurement as described herein,amplifies noise and therefore may be more sensitive to noise episodes,without increasing false positives due to fast, but physiological, ratesof change. Accordingly, a noise episode, or noise episode level, can bedefined by one or more points (e.g., residuals or differentials) above apredetermined threshold, and in some embodiments, for a predeterminedperiod of time. Similarly, a noise level determination can be reduced oraltered when a different (e.g., reduced) number of points above thepredetermined threshold are calculated in a predetermined period oftime.

In some embodiments, the amplitude of total signal, which can also bedescribed as power of the total signal, analyte signal (with or withoutbaseline (e.g., non-constant noise)), and/or non-constant noise, isperiodically or continuously obtained using methods such as aredescribed in more detail elsewhere herein (e.g., RMS method), whereinthe amplitude is a measure of the strength of the signal component. Insome embodiments, signal artifact events are detected by analysis ofamplitudes of various signal components, such as the amplitude of thenon-constant noise component as compared to the amplitude of the analytesignal (with or without baseline).

In some embodiments, a start of a signal artifact event is determinedwhen the amplitude (power) of a signal artifact meets a firstpredetermined condition. In one embodiment, the first predeterminedcondition includes a residual amplitude of at least about 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 14, 16, 18, 20 or 25% of the total signal or analytesignal amplitude (with or without baseline). In another embodiment, thefirst predetermined condition includes a differential amplitude(amplitude of a differential) of at least about 2, 3, 4, 5, 6, 7, 8, 9,10, 12, 14, 16, 18, 20 or 25% of the total signal or analyte signalamplitude (with or without baseline). In some embodiments, the firstpredetermined condition includes a plurality of points (e.g.,non-constant noise signal, residual, or differential) within apredetermined period (e.g., 5, 10, 30, or 60 minutes) above apredetermined threshold (e.g., an amplitude or a percentage amplitude),wherein the plurality of points includes 2, 3, 4, 5, 6, 7, 8 or morevalues.

In some embodiments, an end of a signal artifact event is determinedwhen then the amplitude (power) of a signal artifact meets a secondpredetermined condition. In one embodiment, the second predeterminedcondition includes a residual amplitude of no more than about 2, 3, 4,5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20 or 25% of the total signal oranalyte signal amplitude (with or without baseline). In anotherembodiment, the second predetermined condition includes a differentialamplitude of no more than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16,18, 20 or 25% of the total signal or analyte signal amplitude (with orwithout baseline). In some embodiments, the second predeterminedcondition includes a plurality of points (e.g., non-constant noisesignal, residual, or differential) within a predetermined period (e.g.,5, 10, 30, or 60 minutes) below a predetermined threshold (e.g., anamplitude or a percentage amplitude), wherein the plurality of pointsincludes 2, 3, 4, 5, 6, 7, 8 or more values. Additional description canbe found in US Patent Publication Nos. US-2005-0043598-A1,US-2007-0032706-A1, US-2007-0016381-A1, and US-2007-0033254-A1, each ofwhich is incorporated by reference herein in its entirety.

Auto-Calibration

Some preferred embodiments are configured for auto-calibration of thesensor system, wherein “auto-calibration” includes the use of one ormore internal references to calibrate the sensor system. In someembodiments, auto-calibration includes systems and methods configured tocalibrate the sensor based solely on internal reference values. Forexample, the system can be configured to obtain internal referencevalues by exposing the sensor to one, two or more calibration/referencesolution, as described elsewhere herein. As another example, the sensorcan be configured with a reference sensor disposed adjacent to thecontinuous analyte sensor, wherein both the continuous analyte andreference sensors obtain internal reference values for a substantiallyconstant reference analyte (e.g., O₂), which are then used to calibratethe continuous analyte sensor (see the sections entitled “OpticalDetection” and “Calibration Systems and Methods of CalibratingDual-Electrode Sensors” above). However, in some alternative embodimentsof auto-calibration, one or more external reference values can be usedto complement and/or confirm calibration of the sensor system.

In some preferred embodiments, the system is configured tointermittently expose the sensor to a biological sample; howeverconfigurations of the sensor system that allow continuous exposure ofthe sensor to the biological sample are contemplated. In someembodiments, the system is configured to intermittently or periodicallyexpose the sensor to a reference, however configurations of the sensorsystem that allow one or more independent or non-regular referencemeasurements initiated by the sensor system and/or a user arecontemplated. In the exemplary embodiment of a sensor system such asdescribed with reference to FIGS. 8A to 8C, the system is configured tocycle between a measurement phase and calibration phase (with optionalother phases interlaced therein (e.g., flush and KVO)).

In general, timing of auto-calibration can be driven by a variety ofparameters: preset intervals (e.g., clock driven) and/or triggered byevents (such as detection of a biological sample at a sensor). In someembodiments, one or more of the phases are purely clock driven, forexample by a system configured to control the timing housed within aflow control device, remote analyzer, and/or other computer system. Insome embodiments, one or more of the phases are driven by one or moreevents, including: exposure of the sensor to a biological sample (e.g.,blood) exposure of sensor to a reference (e.g., calibration solution),completion of calibration measurement, completion of analytemeasurement, stability of signal measurement, sensor for detecting abiological sample, and the like.

In one exemplary embodiment, calibration and measurement phases aredriven by cleaning of sensor; namely, systems and methods are configuredto detect when the sensor is in the biological sample and/or in thereference solution (e.g., calibration solution), wherein the system isconfigured to switch to appropriate phase responsive to detection ofthat sample/solution.

In another exemplary embodiment, an AC signal is placed on top of a DCsignal (e.g., in an amperometric electrochemical analyte sensor),wherein systems and methods are configured to analyze an impedanceresponse to the AC signal and detect a biological sample thereby.

In yet another exemplary embodiment, systems and methods are configuredfor analyzing the sensor's signal, wherein a change from a knownreference solution (e.g., a known analyte concentration) can be detectedon the signal, and the switch from the calibration phase to themeasurement phase occur responsive thereto; similarly, the system can beconfigured to switch back to the calibration phase responsive todetection of the known signal value associated with the referencesolution.

In yet another exemplary embodiment, systems and methods are configuredto switch between phases responsive to one or more sensors configured todetect the biological sample and/or reference solution at a particularlocation.

In some embodiments, the sensor system is partially or fully controlledby a clock (e.g., predetermined time intervals), which timing can beconfirmed by any of the events (e.g., triggers or sensors) describedabove.

In one exemplary embodiment, systems and methods are provided to enableauto-calibration of an integrated glucose sensor system with minimaluser interaction. In this exemplary embodiment, the integrated sensorsystem is provided with the components described above, including afluids bag, a flow control device, IV tubing, a flow control device, aremote analyzer, a local analyzer and a sensor/catheter, for example. Atsystem start-up, a health care worker inserts the catheter and sensorinto a host and injects a first reference solution (e.g., zero glucosesaline solution) into the IV tubing, wherein the system is configured toallow a predetermined time period (e.g., 20 minutes) for the firstreference solution to pass through the IV tubing and into the catheter.Subsequently, the health care worker couples the fluids bag to the IVtubing, wherein the fluids bag includes a second reference solution(e.g., 100 mg/dl glucose solution) configured to follow the firstreference solution in the IV line. After injecting the first referencesolution and coupling the second reference solution, the health careworker initiates the integrated sensor system (e.g., through the remoteanalyzer touch screen) after which the integrated sensor systemautomatically calibrates and functions for 24 hours without necessaryuser interface (for system calibration and/or initiation). In someembodiments, the sensor system is re-calibrated every 24 hours byinjection of a new first reference solution (e.g., zero glucose salinesolution).

In the above-described exemplary embodiment, the system is configured tocalibrate the sensor with the first and second reference solution andusing the methods described in the section entitled, “Systems andMethods for Processing Sensor Data.” Additionally, the system isconfigured to automatically detect the difference in signal associatedwith the first and second reference solutions, for example, throughsteady state detection of a difference in signal level.

Methods of Integrated System Set-Up and Initial Use In Vivo

Referring to FIG. 6, in one exemplary embodiment, the present system isconfigured and arranged for continuous analyte detection in thecirculatory system of a host, such as a human, and for fluid infusion.As a non-limiting example, in some embodiments, the continuous analytesensor is a glucose sensor at least partially disposed in a fluidcoupler. In this embodiment, system 600 set-up and installation includesimplanting a catheter into one of the host's peripheral veins, fluidlycoupling the sensor (e.g., including fluid coupler) to the implantedcatheter, fluidly coupling the IV tubing and infusion solution 602 a tothe fluid coupler operatively connected to the sensor, to a controllerand/or display (604 and/or 610), installation of the tubing into theflow control device 604, and initializing the system (e.g., turning onthe flow control device). In some circumstances, an operator (e.g., anurse, doctor or other medical caretaker) prepares a calibrationsolution by injecting an amount of glucose into an IV bag of infusionsolution, such as but not limited to a saline hydration solution, andmixing the contents of the bag. In other circumstances, a commerciallyprepared calibration solution is used. In some circumstances, amedicament, nutrient or other substance may be added to the infusionsolution. The bag of prepared infusion solution 602 a is suspended on anIV stand 612, such as a stand that also supports the flow control device604.

Referring to FIG. 1F, the operator implants a catheter 12 in one of thehost's peripheral veins, such as a vein located in the host's forearm,using standard hospital protocol. Next, the operator grasps the fluidcoupler 20, inserts analyte sensor 14 into the catheter's lumen andfluidly couples the first end 20 a of the fluid coupler to thecatheter's hub 18. Note that the sensor is protected by the slottedsheath 26 during insertion. Advantageously, in some embodiments, thefluid coupler and the slotted sheath are configured and arranged suchthat the slotted sheath prevents blood from coming out of the fluidcoupler's second end, until the slotted sheath is removed (e.g., justprior to connection of the second end 20 b to the IV tubing). Inalternative embodiments, such as that shown in FIGS. 1F-1J, the analytesensor is located within the fluid coupler's lumen and the second endincludes a cap configured and arranged to prevent blood coming out ofthe second end prior to connection of the IV tubing. In someembodiments, the operator (e.g., user) sets up the flow control device,then implants the catheter and sensor and then connects the tubing tothe fluid coupler. In other embodiments, the catheter and sensor areimplanted prior to set-up of the flow control device with subsequentconnection of the IV tubing to the fluid coupler. Either sequence ofevents is acceptable, as well as a matter of personal preference and/orhospital protocol.

In preferred embodiments, the IV tubing 606 is configured and arrangedfor installation into a flow control device 604. In some embodiments,the flow control device and tubing are configured and arranged such asis shown in FIGS. 10A-10D. However, other flow control device and/ortubing configurations are used, in some embodiments. In some embodiment,the flow control device is configured to be moved (e.g., by hand or inresponse to pressing a button) to the gravity flow valve position (e.g.,see FIG. 10C), if it is not already in that position, such that thegroove 803 is not blocked by the roller 802. In preferred embodiments,the valve is configured to automatically move to the gravity flow valveposition at shut-off and/or termination of a sensor session. In otherembodiments, the system is configured such that the valve moves to thegravity flow position when the system is turned on.

In preferred embodiment, the operator fluidly couples the tubingassembly 606 a to the fluid reservoir and/or the fluid coupler. In someembodiments, additional lengths of IV tubing 606 are used to make thesefluid connections, as is known in the art. To install the tubingassembly 606 a, the operator grasp by the connector ends 606 c, 606 dand stretches the tubing therebetween. The operator orients thestretched tubing assembly such that its central portion 606 b alignswith the valve's channel 803 and the tubing's male interconnector (e.g.,connector 606 d) aligns with the valve's female interconnector 809. Theoperator then inserts the tubing assembly into the valve channel andreleases the connectors, such that the tubing assembly's central portionrelaxes to a less stretched (but still stretched and linear)configuration. The operator connects the tubing assembly (e.g., via anoptional length of IV tubing) to the IV solution. Then, the operatorremoves the protective sheath from the sensor by pulling it out of thefluid coupler by its hub 28 and connects the tubing assembly to thefluid coupler's second end (e.g., via an optional length of IV tubing).

In preferred embodiments, the system is configured such that theoperator initiates system start-up after installing the sensor, thetubing, and the like, such as described above. In some embodiments,system initiation and/or start-up include, but are not limited to,turning the system on, selecting a flow profile, entering systemconfiguration information (e.g., type of sensor, type of catheter, typeof infusion solution), entering user information (e.g., patient ID,patient type, patient target analyte levels, etc.). In some embodiments,the system is configured to be initiated when the user presses a button,flips a switch and/or selects (e.g., a start-up protocol) from a menu onthe user interface. In some embodiments, the system is configured toautomatically receive and/or recognize at least some of the start-upinformation, such as via a identification information, a code and/or keyin the interconnection of the tubing assembly and the flow controldevice, via an RFID chip in the patient arm band, via optically scanninga bar code on the patient's chart/arm band and/or on the fluid couplerand/or catheter, and the like. In some embodiments, the flow controldevice system electronics are configured for operator selection of aflow profile from a menu of flow profiles (e.g., 2, 3, 4, 5, 6, 7, 8, 9,10 or more flow profiles). In preferred embodiments, the system isconfigured for selection of a flow profile (by the operator) at leastduring system start-up/initiation. However, in some further embodiments,the system electronics are configured for selection of another profileand/or modification (e.g., re-programming) of the flow profile duringsystem use. For example, if during use of the system, infusion solutionis changed from a first type to a second type (e.g., from saline to aglucose solution), the flow profile can be modified to accommodate thatinfusion solution change.

In some embodiments, the system is configured to begin intermittentlyinfusing the calibration solution and drawing back samples of the host'sblood (e.g., according to the flow profile), energizing the sensor andgenerating measurements of the calibration solution and blood, and thelike, upon system initiation/start-up by the operator. For example,depending upon the flow profile specifications, the flow control devicealternately infuses (e.g., at one or more rates) the calibrationsolution for about 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0 or moreminutes, then draws back a blood sample, returns the sample to the host(e.g., reinfuse the sample), and then returns to infusing thecalibration solution. Calibration measurements are taken during infusionphases of the flow profile. Blood analyte measurements are taken duringdraw-back phases of the flow profile (e.g., when the sensor is bathed ina blood sample). In some embodiments, the sensor is a dual-electrodeglucose sensor, and the system is configured to collect signal(s) fromboth the plus-enzyme (e.g., plus GOX) and no-enzyme working electrodes.

In some embodiments, the system is configured to follow a “break-in”procedure (also referred to as “run-in”). For example, in someembodiments, the system is configured to cycle between infusion andsample draw-back for about 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 1.0, 1.25,1.5, 1.75 or 2-hours. In one embodiments, at about 1-hour, the processormodule is configured to and/or includes programming that evaluatessensor stability (e.g., sensor break-in), such as by evaluating therates of change of the no-enzyme waveform, the amplitude of theno-enzyme signal, and/or the like. In some embodiments, the system isconfigured to prompt the operator for input of a reference blood glucosevalue. For example, in one embodiment, the system is configured to waitabout 1-hour to about 1.25-hours before prompting the operator for areference analyte value. A reference analyte value can be obtained usingany method known in the art. For example, in the case of a continuousglucose sensor, the operator can use a hand-held glucose meter tomeasure the host's blood glucose, and enter the measured value into thesystem via the user interface. In some embodiments, the processor moduleuses one or more entered reference values to calibrate the sensor usingsubstantially time-corresponding sensor measurements. In someembodiments, the system is configured to utilize an entered referencevalue as a b_(offset).

In some embodiments, the system is configured to display the host'sblood glucose concentration in response to the processor moduledetermining that break-in is complete and/or after sensor calibration.For example, if the processor module determines that the sensor signalhas substantially stabilized, the system displays analyte values to theoperator. If, on the other hand, the processor module determines thatthe sensor signal is not yet substantially stabilized, then the systemdoes not display an analyte value to the operator. In somecircumstances, the system is configured to prompt the operator to inputadditional reference analyte values. For example, in one embodiment, thesystem is configured to wait a period of time (e.g., 5, 10, 15, 20, 30,40, 50 or 60 minutes) and then to request a reference analyte value. Ina further embodiment, if the sensor signal has still not stabilized,then the system is configured to wait another period of time (e.g., 5,10, 15, 20, 30, 40, 50 or 60 minutes) and then to request a referenceanalyte value. In another further embodiment, if the sensor signal hasnot substantially stabilized after a programmed period of time (e.g.,1.25, 1.5, 1.75, 2, 2.5, or 3-hours), then the system is configured todeclare a sensor failure and to prompt the user to install a new sensor.

In preferred embodiments, the flow control device is configured toinfuse the calibrant and draw-back samples according to the flow profileselected by the operator. In preferred embodiments, the sensor isconfigured and arranged to generate sensor data, and the processormodule is configured to and/or includes programming that processes thesensor data (e.g., as described elsewhere herein), such that the analyteconcentration of the host's blood is measured in real-time and/ordisplayed on a user interface. In preferred embodiments, the processormodule is configured to and/or includes programming that intermittentlycalibrates (e.g., re-calibrates) the sensor.

EXAMPLES Example 1 Glucose Sensor System Trial in Dogs

Referring now to FIG. 4, glucose sensor systems of the embodiment shownin FIG. 1 were tested in dogs. The glucose sensors were built accordingto the preferred embodiments described herein. Namely, a first sensor(Test 1) was built by providing a platinum wire, vapor-depositing theplatinum with Parylene to form an insulating coating, helically windinga silver wire around the insulated platinum wire (to form a “twistedpair”), masking sections of the electroactive surface of the silverwire, vapor-depositing Parylene on the twisted pair, chloridizing thesilver electrode to form a silver chloride reference electrode, andremoving a radial window on the insulated platinum wire to expose acircumferential electroactive working electrode surface area thereon,this assembly also referred to as a “parylene-coated twisted pairassembly.”

An electrode domain was formed over the electroactive surface areas ofthe working and reference electrodes by dip coating the assembly in anelectrode solution and drying. An enzyme domain was formed over theelectrode domain by subsequently dip coating the assembly in an enzymesolution and drying. A resistance domain was formed over the enzymedomain by spraying the resistance domain solution on the sensorconstruct.

After the sensor was constructed, it was placed in the protective sheathand then threaded through and attached to the fluid coupler.

A second sensor (Test 2) was constructed in the same manner as thefirst, except that the silver wire was disposed within (e.g., coiledwithin) the fluid coupler. Accordingly, only the platinum workingelectrode (a single wire) was inserted into the catheter during theexperiment.

Prior to use, the sensors were sterilized using electron beam.

The forelimb of an anesthetized dog (2 years old, ˜40 pounds) was cutdown to the femoral artery and vein. An arterio-venous shunt was placedfrom the femoral artery to the femoral vein using 14 gauge catheters and⅛-inch IV tubing. A pressurized arterial fluid line was connected to thesensor systems at all times. The test sensor systems (test 1 and test 2)included a 20 gauge×1.25-inch catheter and took measurements every 30seconds. The catheter was aseptically inserted into the shunt, followedby insertion of the sensor into the catheter. A transcutaneous glucosesensor (control) of the type disclosed in U.S. Patent Publication No.US-2006-0155180-A1 was built and placed in the dog's abdomen accordingto recommended procedures. The dog was challenged with continuousincremental IV infusion of a 10% dextrose solution (“glucose challenge”)until the blood glucose concentration reached about 400 mg/dL.

FIG. 4 shows the experimental results. The thick line represents datacollected from the Test 1 sensor. The thin line represents datacollected from the Test 2 sensor. Diamonds represent data collected froma hand-held blood glucose meter (SMBG) sampled from the dog's abdomen.Raw glucose test data (counts) are shown on the left-hand Y-axle,glucose concentrations for the “SMBG” controls are shown on theright-hand y-axle, and time is shown on the X-axle. Each time intervalon the X-axle represents 29-minutes (e.g., 10:04 to 10:33 equals 29minutes). Immediately upon insertion into a catheter, each test sensorbegan collecting data with substantially no sensor equilibration time(e.g., break-in time). Each test sensor responded to the glucosechallenge substantially similarly to the control sensor. For example,each device shows the glucose signal increasing from about 3200 countsat 10:33 to about 6000-6700 counts at 11:31. Then, each device showed arapid decrease in glucose signal, to about 4700 counts at 12:00.Additionally, the response of the test sensors and the control sensorwere substantially similar (e.g., the majority of the test data wassubstantially equivalent to the SMBG data at each time point). Fromthese experimental show that an indwelling glucose sensor system (asdescribed herein) in contact with the circulatory system can providesubstantially continuous glucose monitoring in a clinical setting.

Example 2 Glucose Sensor System Trial in Pigs

Referring now to FIG. 5, four glucose sensor systems of the embodimentshown in FIG. 1 were tested in a pig (˜104 lb), using the protocoldescribed for Example 1, above. Glucose was continuously infused atincreasing rates through a distally placed IV catheter until a readoutof 300-400 mg/dl blood glucose was achieved (total 300 ml of a 10%dextrose IV solution). FIG. 5 shows the experimental results. Linesindicated the data from the four sensors (Test 1 through Test 4).Diamonds represent control measurements made with a hand-held glucosemeter (SMBG). Raw glucose test data (counts) are shown on the left-handY-axle, glucose concentrations for the “SMBG” controls are shown on theright-hand y-axle, and time is shown on the X-axle. Test results showthat though the sensors varied in sensitivity, each test sensorresponded to glucose challenge substantially similarly to the controlsensor (SMBG). These experimental results show that an indwellingglucose sensor system (of the preferred embodiments) in contact with thecirculatory system can substantially continuously track glucose in aclinical setting.

Example 3 Glucose Sensor System with Flow Control Device Trial in Pigs

Referring now to FIG. 17, a glucose sensor was built according to thepreferred embodiments described herein. Namely, a test sensor was builtby providing a platinum wire, vapor-depositing the platinum withParylene to form an insulating coating, helically winding a silver wirearound the insulated platinum wire (to form a “twisted pair”), maskingsections of the electroactive surface of the silver wire,vapor-depositing Parylene on the twisted pair, chloridizing the silverelectrode to form a silver chloride reference electrode, and removing aradial window on the insulated platinum wire to expose a circumferentialelectroactive working electrode surface area thereon, this assembly alsoreferred to as a “parylene-coated twisted pair assembly.”

An electrode domain was formed over the electroactive surface areas ofthe working and reference electrodes by dip coating the assembly in anelectrode solution and drying. An interference domain was formed overthe electrode domain by subsequently dip coating the assembly in aninterference domain solution and drying. An enzyme domain was formedover the interference domain by subsequently dip coating the assembly inan enzyme solution and drying. A resistance domain was formed over theenzyme domain by spraying the resistance domain solution on the sensorconstruct.

The test sensor was then located within a 20 gauge catheter and insertedin the femoral vein of a non-diabetic pig. The catheter was connected toan integrated sensor system 600 of the preferred embodiments. The flowcontrol device 604 (e.g., a roller valve as depicted in FIGS. 8A-8C) wasconfigured to move between steps one and two, as described in thesection entitled “Flow Control Device Function,” above. A 107-mg/dLglucose solution was used to calibrate the sensors (e.g., flows from thereservoir 602, through the tubing 606, to the catheter 12). To mimic adiabetic's hyperglycemic state, a gradual infusion of 26% dextrose wasgiven, until the pig's blood glucose was about 600 mg/dl. Then to mimica hypoglycemic state, 10 U Humulin N was given, until the pig's bloodglucose was about 50 mg/dl. Then, the pig's blood glucose was raised toabout 100 mg/dl by a second 26% dextrose infusion.

FIG. 17 is a graphical representation showing uncalibrated glucosesensor data and corresponding blood glucose values over time in a pig.Raw counts are represented on the left Y-axis. Glucose concentration isshown on the right Y-axis. Time is shown on the X-axis. Testmeasurements (e.g., measurements of blood glucose concentration obtainedwith the test sensor, raw counts) are shown as small, black dots.Control measurements (e.g., jugular vein blood samples analyzed on aYellow Springs Instrument (YSI) glucose analyzer) are shown as diamonds.

During the experiment, the system was configured to alternate betweencalibration measurements (with the 107 mg/dl glucose solution) and bloodglucose measurements, as described in the sections entitled “Step one:Contacting Sensor with Calibration Solution and Calibration” and “StepTwo: Sample Collection and Measurement,” respectively. Accordingly, asthe experiment proceeded the test signal oscillated between calibrationsolution (107 mg/dl) and blood glucose measurements. The sensor (test)blood glucose measurement correlated tightly with the control bloodglucose measurements. For example, as the pig's blood glucoseconcentration increased (due to infusion of glucose), so did the testmeasurements, reaching about 550 mg/dl at about 12:20. Similarly, as thepig's blood glucose concentration decreased (due to infusion ofinsulin), so did the test measurements, decreasing to about 50 mg/dl atabout 14:45.

From these data, it was concluded that a glucose sensor system of thepreferred embodiments (including a valve as described with reference toFIGS. 8A to 8C) accurately and sensitively measures intravenous glucoseconcentration over a wide dynamic range.

Example 4 Glucose Sensor System with Flow Control Device Trial in Humans

Referring now to FIG. 18, a glucose sensor, constructed as described inExample 3, and an integrated sensor system (as described in Example 3)were tested in a volunteer, diabetic host. The flow control device wasconfigured as shown in FIGS. 8A-8C. The system was configured toalternate between a calibration phase and a blood glucose measurementphase, as described elsewhere herein. At sensor/catheter initialization,a 0 mg/dl glucose saline solution filled syringe was injected into theIV tubing and the fluids bag including 100 mg/dl glucose heparinizedsaline solution was subsequently coupled to the tubing. The system wasthen turned on (e.g., sensor initialized). The 0 mg/dl glucose salinesolution passed over the sensor, after which the 100 mg/dl glucoseheparinized saline solution subsequently passed over the sensor allowingfor initial calibration information to be collected. The system,including a flow control device as described with reference to FIGS. 8Ato 8C, then oscillated between exposure of the sensor to a blood sampleand exposure of the sensor to the 100 mg/dl glucose heparinized salinesolution. The sensor auto-calibrated by a combination of calibrationinformation obtained from measurement of the 0 mg/dl-glucose and 100mg/dl-glucose saline solutions and the step-change-response of thesensor to the blood sample, according to the methods described in thesection entitled “Systems and methods for Processing Sensor Data.” Noexternal measurements (e.g., blood glucose measurements by YSI or fingerstick) were used to calibrate the system in this example. During theexperiment, the flow control device cycled between step one (measuringthe 100 mg/dl-glucose solution) and step two (blood sample take up andmeasuring the blood glucose concentration), such that one cycle wascompleted every 5-minutes. The experiment was conducted for a period ofabout 2.5 days. The host followed her usual schedule of meals andinsulin injections.

FIG. 18 is a graphical representation showing calibrated venous bloodglucose sensor measurements (test, black dots) and corresponding controlblood glucose measurements (YSI, large circles) over time in thevolunteer diabetic host. Glucose concentration is shown on the Y-axisand time on the X-axis. Test measurements tracked closely with controlmeasurements, ranging from about 350 mg/dl, at about 10:00 and about15:30, to about 50 mg/dl, at about 11:45. From these data, it has beenconcluded that 1) the sensor calibration methods of the preferredembodiments accurately calibrate the sensor and 2) the glucose sensorsystem of the preferred embodiments accurately measures intravenousglucose concentration over a wide dynamic range, for two or more days,in humans.

Example 5 Detection of Crosstalk In Vitro

In general, crosstalk in dual-electrode sensors can be examined byrecording the signal detected at each working electrode while placingthem in a series of analyte solutions. This example describes oneexemplary in vitro test for crosstalk on a dual-electrode analytesensor. A variety of dual-electrode analyte sensors can be tested forcrosstalk, using this method.

First, the sensor to be tested is placed in a phosphate buffered saline(PBS) for several minutes, such as until a stable signal is detectedfrom both working electrodes. Next, the sensor is challenged withglucose solutions and optionally with one or more known noise-causingsubstances. For example, sensor can be placed sequentially in a seriesof glucose solutions (e.g., 40-mg/dl, 200-mg/dl and 400-mg/dl glucose inPBS) and the signals from the two working electrodes graphed.

If there is no crosstalk between the working electrodes, then, as thesensor is placed in solutions of increasingly higher glucoseconcentration, the graphed signal of the Plus GOx electrode should showcorresponding signal increases, while the No GOx electrode signal shouldexhibit little or no change in signal. However, when the sensor isplaced in a solution of a known noise-causing species (e.g.,acetaminophen, ibuprofen, vitamin C, urea, and the like), both workingelectrodes (Plus GOx and No GOx) should exhibit an increase in signal.In some circumstances, this increase in signal is a dramatic spike insignal.

If there is crosstalk, then the signals from both electrodes shouldincrease as the sensor is moved to solutions of increased glucoseconcentration. Similarly, when the sensor is placed in a solution of aknown noise-causing species, both working electrodes should exhibit anincrease in signal.

Example 6 Effect of Electroactive Surface Size in Dual-Electrodes InVivo

The effect of size of the electroactive surfaces (of the workingelectrodes) on noise measurement was examined in non-diabetic humanhosts. Sensors having electroactive surfaces of different sizes, andlacking GOx in the enzyme layer were constructed as follows. Clean,insulated Pt/Ir wires were separated into two groups. For Group 1,0.029″ of the insulation was removed from each wire (e.g., about itsentire circumference), to expose electroactive surfaces. For Group 2,the same procedure was performed, except that two sequential 0.029″portions of the insulation were removed; effectively doubling the sizeof the Group 2 electroactive surfaces relative to those of Group 1.After exposure of the electroactive surfaces, the two groups of wireswere treated identically. On each wire, a portion of the sensor'smembrane was fabricated by the sequential application (and curingthereof) of electrode domain, enzyme domain and resistance domainmaterials. The enzyme domain material contained no active GOx, so thatthe sensors would be able to detect only noise (no analyte). Next, pairsof wires (e.g., two Group 1 wires or two Group 2 wires) were alignedsuch that the electroactive surfaces were parallel to each other, andthen twisted together. An Ag/AgCl ribbon was wrapped around a portion ofthe twisted wires (to form the reference electrode), and then additionalresistance domain material was applied to the assembly. Each hostconsumed 1,000-mg of acetaminophen near the end of the trial, so thatthe affect of a known interferent could be examined.

FIG. 19A is a graph illustrating the in vivo experimental results fromimplantation of a Group 1 sensor (one 0.029″ electroactive surface areaper electrode). The Y-axis represents raw counts and the X-axisrepresents time. The data collected from each electroactive surface isshown as a line (E1, No GOx and E2, No GOx). Please note that the datarepresents only the noise component of the signal. No analyte componentwas detected, due to the lack of GOx in the portions of the membraneadjacent to the electroactive surfaces. Referring now to FIG. 19A, thenoise signal detected by each of the working electrodes (E1, E2)fluctuated widely throughout the implantation time. The amplitude of thenoise component detected by E2 was substantially greater than the noisecomponent detected by E1. For example, referring to the data circled byoval A, the noise signal peaks detected by E2 were substantially greaterthan those detected by E1. Additionally, the noise fluctuations betweenthe two working electrodes were not always in the same direction. Forexample, referring to the data circled by oval B, the E2 noise signalcomponent increased while the E1 noise signal component decreased. Whenthe sensor was challenged with acetaminophen (drug consumption indicatedby the arrow), both electrodes registered a substantial increase innoise signal, wherein the shapes of the curves were substantiallysimilar. However, E1 detected a substantially lower total amount ofnoise when compared with that detected by E2; this difference in signalamplitude (in response to a non-biologic interferent) indicates that thesignals (e.g., on the two working electrodes) did not have substantiallysimilar sensitivities.

FIG. 19B is a graph illustrating the in vivo experimental results fromimplantation of a Group 2 sensor (two 0.029″ electroactive surface areasper electrode). As described above, the Group 2 electroactive surfacesare about two-times as large as those of the Group 1 sensors. As before,the Y-axis represents raw counts and the X-axis represents time, and thedata collected from each electroactive surface is shown as a line (E1,No GOx and E2, No GOx). As before, the data represents only the noisecomponent of the signal. No analyte component was detected, due to thelack of GOx in the portions of the membrane adjacent to theelectroactive surfaces. Referring now to FIG. 19B, the noise signaldetected by each of the working electrodes (E1, E2). Throughout thecourse of the experiment (˜20-hours), noise signals detected by E1 andE2 tracked very closely throughout the entire experiment. Namely, thenoise signals detected by E1 and E2 were of substantially the sameamplitude and followed substantially similar fluctuations, varying fromabout 7,000 counts (at 4:00 PM) to about 4500 counts (from about 6:30 AMto about 9:00 AM). Even when the Group 2 sensor was challenged withacetaminophen (a known non-biological interferent that should cause afalse signal on the sensor), the working electrodes recordedsubstantially equal signal amplitudes (˜6,900 counts) and followedsubstantially similar wave forms having substantially equivalentamplitudes; these data indicate that the two working electrodes hadsubstantially equal sensitivities.

From these data, the inventors concluded that the electroactive surfacesof a dual-electrode glucose sensor must be sufficiently large in orderfor the two electrodes to detect substantially equal noise signalcomponents. For example, in this experiment, the electroactive surfacesof the Group 1 working electrodes, which did not measure noiseequivalently, were 0.029″ (e.g., along the electrode's length); whileelectroactive surfaces of the Group 2 working electrodes, which didmeasure noise substantially equivalently, were two times as large (e.g.,2×0.029″=0.058″ along the electrode's length) as those of the Group 1working electrodes.

Example 7 Effect of Electroactive Surface Spacing in Dual-Electrodes InVivo

The effect of the spacing of the electroactive surfaces (of the workingelectrodes) on noise measurement was examined in non-diabetic humanhosts. Sensors having two different configurations were built andtested. Sensors of Configuration 1 (Config. 1) included Plus GOx and NoGOx working electrodes with non-aligned (e.g., miss-aligned, skewed)electroactive surfaces. In other words, the electroactive surfaces werespaced such that, in the completed sensor, one electroactive surfacewould be more proximal to the sensor's tip than then other. Sensors ofConfiguration 2 (Config. 2) also included Plus GOx and No GOx workingelectrodes, except that the electroactive surfaces were closely aligned(e.g., parallel). In Config. 2, the membrane was the insulator betweenthe two working electrodes, enabling the very close spacing (i.e., thethickness of the membrane determined the spacing between the two workingelectrodes, between about 0.001 inches to about 0.003 inches between thetwo working electrodes.)

Config. 1 sensors were fabricated as follow. For each sensor, two clean,insulated Pt/Ir wires were wound together (and an Ag/AgCl ribbon twistedthere around), followed by removal of a portion of the insulatingmaterial from each wire to create the electroactive surfaces. Theelectroactive surfaces were offset (e.g., not next to each other)relative to the sensor's tip. The twisted wire pairs were then dipped inenzyme domain solution (including GOx) just far enough such that onlythe electroactive surface closest to the tip of the sensor was coatedwith the enzyme domain material (e.g., E1, Plus GOx). The electroactivesurface farthest from the sensor tip was not coated with the enzymedomain material (e.g., E2, No GOx). After curing, resistance domainmaterial was applied to the twisted pairs of wires.

Config. 2 sensors were fabricated as follow. Clean, insulated Pt/Irwires were divided into two groups. Electrode and enzyme (Plus GOx)domain materials were sequentially applied to the E1, Plus GOx workingelectrode wires. Electrode and enzyme (No GOx) domain materials weresequentially applied to the E2, No GOx working electrode wires.Resistance domain material was applied to all wires individually (e.g.,to form independent/discontinuous first and second resistance domains).After the resistance domain material was cured, one each of the E1, PlusGOx and E2, No GOx were placed together such that the wires'electroactive surfaces were aligned, and then twisted together to form atwisted pair. An Ag/AgCl ribbon was wrapped around each twisted pair(but not covering the electroactive surfaces), followed by applicationof a continuous resistance domain (e.g., a third resistance domain) overthe sensor. The resulting sensors included a coaxial helix configurationsimilar to that shown in FIG. 18 of U.S. Patent Publication No.US-2008-0083617-A1, incorporated herein by reference in its entirety.

FIG. 20A is a graph illustrating the in vivo experimental results fromimplantation of a Config. 1 sensor (non-aligned electroactive surfaces).The Y-axis represents raw counts and the X-axis represents time. The E1,Plus GOx electrode detected both glucose and noise signal componentswhile the E2, No GOx electrode detected only the noise signal component.Throughout most of the experiment's duration, the two working electrodesrecorded signals having somewhat similar waveforms with the two linesbeing relatively flat with little fluctuation in amplitude (thevolunteer was not diabetic, and thus would generally not have largefluctuations in glucose level). During the acetaminophen challenge, theE1, Plus GOx signal rapidly peaked at about 12,000 counts and thengradually declined, while the E2, No GOx signal peak was much lower inamplitude (˜6,000 counts).

FIG. 20B is a graph illustrating the in vivo experimental results fromimplantation of a Config. 2 sensor (aligned electroactive surfaces). TheY-axis represents raw counts and the X-axis represents time. In general,the E1, Plus GOx electrode detected both glucose and noise signalcomponents while the E2, No GOx electrode detected only the noise signalcomponent. Throughout most of the experiment's duration, the twoelectrodes recorded signals having substantially similar waveforms;though the E1, Plus GOx electrode signal was generally higher inamplitude than that of the E2, No GOx electrode. When the sensor waschallenged with acetaminophen, the signals of both working electrodesrapidly peaked at about 11,000-12,000 counts (e.g., the amplitudes ofthe two peaks were substantially equivalent/similar) and then graduallydeclined.

From these data, the inventors concluded that the electroactive surfacesof a dual-electrode glucose sensor must be sufficiently close togetherin order for the two electrodes to detect substantially equivalent noisesignal components. Additionally, the inventors concluded that for adual-electrode sensor including the combination of a continuousresistance domain disposed over discontinuous resistance domains (e.g.,applied independently to the two working electrodes) the detected signalamplitudes more closely correspond to each other. This improvesmathematical noise correction by enabling better noise signalsubtraction.

Example 8 Use of Dual-Electrode Glucose Sensors in Intravenous PorcineModel

Six dual-electrode glucose sensor IV systems, including a dual-electrodeglucose sensor (e.g., including a first working electrode E1 (e.g.,configured to generate signals associated with both glucose andnon-glucose-related species having oxidation/reduction potentials thatoverlap with that of glucose) and a second working electrode E2 (e.g.,configured to generate signals associated with non-glucose-relatedspecies having oxidation/reduction potentials that overlap with that ofglucose)) and a fluid control system (including a catheter inserted intoa peripheral vein) were tested in a porcine model, as describedelsewhere herein. A 100-mg/dl-glucose solution was used to calibrate andwash the dual-electrode sensor, according to procedures describedelsewhere herein. To obtain an increase in serum glucose tohyperglycemic ranges, a 22.5% dextrose solution was gradually infusedthrough the animal's left ear vein. The infusion was stopped once theblood glucose levels reached sufficiently high blood glucose values anda return to normal values was followed. Blood samples were collected in5-minute intervals from the right jugular vein throughout the study.Plasma glucose values were determined on an YSI instrument. The studytook about 4-hours.

FIG. 21A is a graph illustrating test results from an exemplarydual-electrode continuous glucose sensor coupled to a flow controlsystem via a catheter inserted in the animal's femoral vein. The Y-axisrepresents glucose values (mg/dl) and the X-axis represents time. Thesmall triangle represents glucose values provided by the dual-electrodeglucose sensor system every 5 minutes, while the small diamondrepresents substantially time-corresponding control glucose valuesobtained from the YSI device.

FIG. 21B is a Clark Error Grid quantifying the clinical accuracy of theblood glucose estimates generated by the dual-electrode glucose sensorsystem as compared to a reference value (e.g., YSI). All values fallwithin area “A,” which indicates that all values provided by thedual-electrode sensor are within 20% of the values provided by the YSIcontrol test device. R²=0.9799.

The dual-electrode glucose sensor tracked the animal's glucose values,from about 50-mg/dl to about 300-mg/dl over a period of about 4-hours.The signals generated by the first and second working electrodes wereprocessed to provide the data shown in FIGS. 21A-21B. The glucose valuesprovided by the dual-electrode sensor tracked very closely with thecontrol measurements provided by the YSI device. Additionally, allglucose values provided by the dual-electrode glucose sensor fell withinthe “A” portion of the Clark Error Grid. The sensor had an MARD of 7.5%and met the FDA's ISO standard for hand-held glucose monitors (±15-mg/dlor ±20%) by 100%.

From these data, the investigators concluded that continuous IV glucosetracking (via a peripheral vein) using a dual-electrode continuousglucose sensor, including first and second working electrodes configuredas described herein, coupled with a catheter and a flow control systemcan provide consistently accurate glucose values in vivo.

Example 9

In vivo glucose data was generated using a dual-electrode glucose sensorimplanted in a host's peripheral vein, as described elsewhere herein. Aflow control system, such as that described with reference to FIGS.7-8C, was installed, including a reference glucose infusion solution(e.g., 100-mg/dl glucose). Upon initiation, the flow control devicebegan drawing back blood samples to the glucose sensor, re-infusing thesamples and infusing the reference solution, such as according to theprogrammed flow profile. Data were received from the plus-enzyme andno-enzyme working electrodes, such as described elsewhere herein. Thesignal waveforms of the non-enzyme working electrode data (e.g., secondsignal waveform) were evaluated to determine if the draw-back/infusionwas successful. For exemplary purposes, one second signal waveform (fromthe no-enzyme working electrode) generated during a known successfulinfusion and one second signal waveform generated during a knownunsuccessful infusion are presented.

FIG. 22 is a graph of a second signal waveform (e.g., no-enzyme workingelectrode data) generated during a successful infusion of the referencesolution into the host versus the adaptive calibration waveformtemplate. Line 2202 is the adaptive calibration waveform template. Line2204 represents the second signal waveform generated on the non-enzymeelectrode during infusion of the reference solution into the host. Theportion of the graph denoted by 2206 represents the data that could beused to calibrate the sensor, if the second signal waveform met at leastone criterion. For example, in this experiment, the second signalwaveform substantially overlapped with the adaptive waveform template.Additionally, the second signal waveform was substantially monotonic,like the adaptive waveform template. These facts indicated that theinfusion was successful. The second signal waveform was integrated intothe adaptive waveform template, to generate an updated adaptive waveformtemplate. Additionally, a data value was displayed on the system's userinterface.

FIG. 23 is a graph of a second signal waveform generated during anunsuccessful infusion of the reference solution into the host versus theadaptive calibration waveform template. Line 2302 represents theadaptive calibration waveform template. Line 2304 represents the secondsignal waveform generated on the non-enzyme electrode during theunsuccessful infusion of the reference solution into the host. Theportion of the graph denoted by 2306 represents the data that could havebeen used to calibrate the sensor, if the second signal waveform had metat least one criterion. Lines 2302 and 2304 substantially overlapped andhad a negative slope, until about 70 sample points. At about 70 samplepoints, line 2304 exhibited a substantial peak. A second increase beganat about 110 sample points and extended to 120 sample points, when thewaveform ended. During this deviation (e.g., 2306) the second signalwaveform did not correlate with the adaptive template. Additionally, thesecond signal waveform was not monotonic. These data indicated that theinfusion was not successful and the system was not reliable. The signalwaveform was not integrated with the adaptive template. The signal datadenoted by 2306 and corresponding generated first signal data were notused to calibrate the sensor.

Example 10

In vivo glucose data was generated using a dual-electrode glucose sensorimplanted in a host's peripheral vein, as described elsewhere herein. Aflow control system, such as that described with reference to FIGS. 7-8Cwas installed, including a reference glucose infusion solution (e.g.,100-mg/dl glucose). Upon initiation, the flow control device begandrawing back blood samples to the glucose sensor, re-infusing thesamples and infusing the reference solution, such as according to theprogrammed flow profile.

FIG. 24 is a graph of the signal generated from the plus-enzyme workingelectrode (black diamonds) and from the no-enzyme working electrode(black dots). Completion of sensor break-in is denoted by the dashedvertical line. The sensor was implanted in the host at about 2:00 P.M.Upon drawing-back a sample, the signal waveform increased. Uponre-infusion of the sample and infusion of the reference solution, thesignal waveform decreased. Accordingly, with each cycle of sampledraw-back and infusion, a signal peak and valley were generated. Uponsensor start-up, the sensor signal (e.g., baseline), on both workingelectrodes, started high (e.g., ˜400-500 counts) and then driftedprogressively downward over time (e.g., baseline drift). In thisexample, wherein the sensor system included a dual electrode sensor, andboth electrochemical break-in (illustrated by the exponential decayduring the first 30 minutes after sensor start-up) and membrane break-in(illustrated by a difference between the enzyme signal and non-enzymesignal during the first 30 minutes after sensor start-up) can be seen.After about the first 30 minutes, the sensor data, notably the secondsignal waveform (e.g., no-enzyme working electrode data), stabilized.

Example 11

In vivo glucose data was generated using a dual-electrode glucose sensorimplanted in a host's peripheral vein, as described elsewhere herein. Aflow control system, such as that described with reference to FIGS. 7-8Cwere installed, including a reference glucose infusion solution (e.g.,100 mg/dL glucose). Upon initiation, the flow control device begandrawing back blood samples to the glucose sensor, re-infusing thesamples and infusing the reference solution, such as according to theprogrammed flow profile.

FIG. 25 is a graph of calculated sensor sensitivities. The Y-axisrepresents sensor sensitivity (in pA/mg/dL). The X-axis represents time(e.g., of sensor implantation/use). Each point represents an individualsensitivity calculation determined using a subtracted signal from thedual-electrode sensor, wherein the sensitivity was determined when thesensor was exposed to the 100 mg/dL reference solution, as described inmore detail elsewhere herein. Change in calculated sensor sensitivitywas evaluated over short time periods (e.g., also referred to asshort-term sensitivity evaluation; every 5-minutes) throughout sensoruse, and over longer time periods (e.g., also referred to as long-termsensitivity evaluation) the total change in sensor sensitivity betweenthe calculated sensor sensitivity at t=0 and at t=1-hr, and betweent=1-hr and t=2-hr). The change in sensitivity was calculated using theformula (m₂−m₁)/m₁. For the first hour of sensor use, when the sensorwas breaking in and dramatic changes in sensitivity are observed, achange in sensitivity threshold was set at ±100% over the hour. For thesecond hour of sensor use, when changes in sensitivity begin to leveloff, the threshold was set at ±20%. For short time sensitivityevaluation, the threshold was set at a ±15% change in sensor sensitivityover 5-minutes. An example of 5 minute time period is shown at 2502. Thecalculated sensitivity at point 2502 a was 2.2 pA/mg/dL and thecalculated sensitivity at point 2502 b was also 2.2 pA/mg/dL, resultingin a sensitivity change of 0% in 5-minutes. Accordingly, the change insensitivity between these two time points was well within the ±15% per5-minutes threshold. An example of sensitivity drift during the firsthour of sensor use is denoted by 2504. At 2504 a, the sensitivity was1.5 pA/mg/dL. At 2504 b, the sensitivity was about 2.2 pA/mg/dL, givinga 70% change in sensitivity over the first hour of sensor use.Accordingly, the increase in sensor sensitivity, during the first hourof sensor use, was within the ±100% threshold. Another example ofsensitivity drift, during the second hour of sensor use, is denoted by2506. For the second hour of sensor use, the threshold was set at ±20%over the second hour. Again, at 2504 b, the sensitivity was about 2.2pA/mg/dL. At point 2506 a, the sensitivity was 2.4 pA/mg/dL, giving a20% drift in sensitivity, which met the ±20% threshold.

Example 12 Pain Monitoring by Continuous Intra-Vascular GlucoseDetection in the Neonatal Host

A newborn infant (the host) is transferred to the newborn intensive careunit (NICU) soon after birth. When the host arrives, a nurse inserts a24-gauge catheter into one of the host's veins. The nurse inserts acontinuous glucose sensor (e.g., see FIG. 1F) into the catheter andconnects the fluid coupler to the catheter's hub. The sensor isconfigured such that it extends into the catheter's lumen such that theelectroactive surface(s) are located adjacent to the catheter's orifice.Then the nurse sets up the fluid control device (e.g., see FIG. 10A)with an infusion solution, and connects the IV tubing to the fluidcoupler. The nurse initiates the system and selects a flow profileoptimized for a neonatal host. For example, the flow profile directs thedrawback of minimum sample volumes (e.g., about 1, 2, 3, 4 or 5-μl),return of the sample to the host, and sensor washing using minimumvolumes (e.g., about 10, 20, 30, 50 or 100-μl of solution). The systembegins continuously monitoring the host's blood glucose level and todisplay the host's blood glucose level. After a period of time, thehost's blood glucose begins to rise. The host's blood glucose exceeds afirst programmed range (e.g., a euglycemic range) and the processormodule provides an alarm to the nurse and/or to display at least one ofan instruction to the nurse, the host's glucose level, and an indicationof the host's level of comfort (e.g., pain, distress), wherein the levelof the comfort is associated with the host's glucose concentration. Forexample, the nurse is alerted that the host is beginning to becomedistressed and may be feeling pain. The system is configured to instructthe nurse to check the host's vital signs and to provide appropriatecare for the host's observed condition. The host's blood glucosecontinues to increase and exceeds a second programmed range (e.g., ahyperglycemic range). The system provides an alarm, which alerts thenurse to an increase in the host's distressed condition. Additionally,the system displays at least one of updated instructions to the nurse,the host's blood glucose level, and/or an indication of the host's painlevel, wherein the pain level is associated with the host's bloodglucose level. Upon checking on the host, the nurse observes that thehost appears to be in pain, and follows instructions displayed on thedisplay to administer pain medication. Alternatively, the system can beconfigured to automatically infuse basal and/or bolus amounts of painmedication based at least in part on the measured glucose concentration.As the pain medication becomes effective, the host's blood glucosebegins to return to the first programmed range. The system displays atleast one of the host's blood glucose level and/or an indication of thehost's comfort (e.g., pain, distress) level, wherein the indication ofthe host's comfort level is associated with the host's glucose level.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. Pat. No.4,994,167; U.S. Pat. No. 4,757,022; U.S. Pat. No. 6,001,067; U.S. Pat.No. 6,741,877; U.S. Pat. No. 6,702,857; U.S. Pat. No. 6,558,321; U.S.Pat. No. 6,931,327; U.S. Pat. No. 6,862,465; U.S. Pat. No. 7,074,307;U.S. Pat. No. 7,081,195; U.S. Pat. No. 7,108,778; U.S. Pat. No.7,110,803; U.S. Pat. No. 7,192,450; U.S. Pat. No. 7,226,978; U.S. Pat.No. 7,310,544; U.S. Pat. No. 7,364,592; U.S. Pat. No. 7,366,556; andU.S. Pat. No. 7,424,318.

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Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. patentapplication Ser. No. 09/447,227 filed Nov. 22, 1999 and entitled “DEVICEAND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. patent application Ser.No. 11/654,135 filed Jan. 17, 2007 and entitled “POROUS MEMBRANES FORUSE WITH IMPLANTABLE DEVICES”; U.S. patent application Ser. No.11/654,140 filed Jan. 17, 2007 and entitled “MEMBRANES FOR AN ANALYTESENSOR”; U.S. patent application Ser. No. 11/691,426 filed Mar. 26, 2007and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No.12/103,594 filed Apr. 15, 2008 and entitled “BIOINTERFACE WITH MACRO-AND MICRO-ARCHITECTURE”; U.S. patent application Ser. No. 12/113,724filed May 1, 2008 and entitled “LOW OXYGEN IN VIVO ANALYTE SENSOR”; U.S.patent application Ser. No. 12/055,098 filed Mar. 25, 2008 and entitled“ANALYTE SENSOR”; U.S. patent application Ser. No. 12/054,953 filed Mar.25, 2008 and entitled “ANALYTE SENSOR”; U.S. patent application Ser. No.12/055,114 filed Mar. 25, 2008 and entitled “ANALYTE SENSOR”; U.S.patent application Ser. No. 12/133,789 filed Jun. 5, 2008 and entitled“INTEGRATED MEDICAMENT DELIVERY DEVICE FOR USE WITH CONTINUOUS ANALYTESENSOR”; U.S. patent application Ser. No. 12/133,761 filed Jun. 5, 2008and entitled “INTEGRATED MEDICAMENT DELIVERY DEVICE FOR USE WITHCONTINUOUS ANALYTE SENSOR”; U.S. patent application Ser. No. 12/133,738filed Jun. 5, 2008 and entitled “INTEGRATED MEDICAMENT DELIVERY DEVICEFOR USE WITH CONTINUOUS ANALYTE SENSOR”; U.S. patent application Ser.No. 12/139,305 filed Jun. 13, 2008 and entitled “ELECTRODE SYSTEMS FORELECTROCHEMICAL SENSORS”; U.S. patent application Ser. No. 12/175,391filed Jul. 17, 2008 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S.patent application Ser. No. 12/182,008 filed Jul. 29, 2008 and entitled“INTEGRATED RECEIVER FOR CONTINUOUS ANALYTE SENSOR”; U.S. patentapplication Ser. No. 12/182,073 filed Jul. 29, 2008 and entitled“INTEGRATED RECEIVER FOR CONTINUOUS ANALYTE SENSOR”; U.S. patentapplication Ser. No. 12/182,083 filed Jul. 29, 2008 and entitled“INTEGRATED RECEIVER FOR CONTINUOUS ANALYTE SENSOR”; U.S. patentapplication Ser. No. 12/195,191 filed Aug. 20, 2008 and entitled “SYSTEMAND METHODS FOR PROCESSING ANALYTE SENSOR DATA”; U.S. patent applicationSer. No. 12/195,773 filed Aug. 21, 2008 and entitled “SYSTEM AND METHODSFOR PROCESSING ANALYTE SENSOR DATA”; U.S. patent application Ser. No.12/247,137 filed Oct. 7, 2008 and entitled “IMPLANTABLE ANALYTE SENSOR”;U.S. patent application Ser. No. 12/250,918 filed Oct. 14, 2008 andentitled “ANALYTE SENSOR”; U.S. patent application Ser. No. 12/253,125filed Oct. 16, 2008 and entitled “SIGNAL PROCESSING FOR CONTINUOUSANALYTE SENSOR”; U.S. patent application Ser. No. 12/253,120 filed Oct.16, 2008 and entitled “SIGNAL PROCESSING FOR CONTINUOUS ANALYTE SENSOR”;U.S. patent application Ser. No. 12/253,064 filed Oct. 16, 2008 andentitled “SIGNAL PROCESSING FOR CONTINUOUS ANALYTE SENSOR”; U.S. patentapplication Ser. No. 12/252,996 filed Oct. 16, 2008 and entitled “SIGNALPROCESSING FOR CONTINUOUS ANALYTE SENSOR”; U.S. patent application Ser.No. 12/252,967 filed Oct. 16, 2008 and entitled “SIGNAL PROCESSING FORCONTINUOUS ANALYTE SENSOR”; U.S. patent application Ser. No. 12/252,952filed Oct. 16, 2008 and entitled “SIGNAL PROCESSING FOR CONTINUOUSANALYTE SENSOR”; U.S. patent application Ser. No. 12/260,017 filed Oct.28, 2008 and entitled “SENSOR HEAD FOR USE WITH IMPLANTABLE DEVICES”;U.S. patent application Ser. No. 12/258,320 filed Oct. 24, 2008 andentitled “SYSTEMS AND METHODS FOR PROCESSING SENSOR DATA”; U.S. patentapplication Ser. No. 12/263,993 filed Nov. 3, 2008 and entitled “SIGNALPROCESSING FOR CONTINUOUS ANALYTE SENSOR”; U.S. patent application Ser.No. 12/264,835 filed Nov. 4, 2008 and entitled “IMPLANTABLE ANALYTESENSOR”; U.S. patent application Ser. No. 12/258,235 filed Oct. 24, 2008and entitled “SYSTEMS AND METHODS FOR PROCESSING SENSOR DATA”; U.S.patent application Ser. No. 12/258,345 filed Oct. 24, 2008 and entitled“SYSTEMS AND METHODS FOR PROCESSING SENSOR DATA”; U.S. patentapplication Ser. No. 12/258,325 filed Oct. 24, 2008 and entitled“SYSTEMS AND METHODS FOR PROCESSING SENSOR DATA”; U.S. patentapplication Ser. No. 12/258,318 filed Oct. 24, 2008 and entitled“SYSTEMS AND METHODS FOR PROCESSING SENSOR DATA”; U.S. patentapplication Ser. No. 12/258,335 filed Oct. 24, 2008 and entitled“SYSTEMS AND METHODS FOR PROCESSING SENSOR DATA”; U.S. patentapplication Ser. No. 12/264,160 filed Nov. 3, 2008 and entitled “DUALELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR.”

All references cited herein, including but not limited to published andunpublished applications, patents, and literature references, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

1. A method for performing a diagnostic of an analyte sensor system,comprising: providing a sensor system comprising an analyte sensor and aflow control device configured to intermittently expose the analytesensor to a biological sample and an infusion solution, wherein theanalyte sensor comprises: a first working electrode configured toprovide a first signal comprising an analyte component and a baselinecomponent; and a second working electrode configured to provide a secondsignal comprising a baseline component substantially without an analytecomponent; and evaluating the sensor system based at least in part onthe second signal.
 2. The method of claim 1, wherein the second signalcomprises a signal waveform, and wherein the step of evaluating thesensor system comprises evaluating the signal waveform for at least oneof an expected shape and a pattern when the analyte sensor is exposed toat least one of the biological sample and the infusion solution.
 3. Themethod of claim 2, wherein the step of evaluating the signal waveformcomprises evaluating at least one of a similarity and a correlationbetween the signal waveform and a waveform template.
 4. The method ofclaim 3, wherein the waveform template is based at least in part on apriori information.
 5. The method of claim 3, wherein the waveformtemplate is based at least in part on a signal waveform measured by thesensor system.
 6. The method of claim 3, wherein the step of evaluatingat least one of a similarity and a correlation of the signal waveform toa waveform template comprises performing a correlation waveformanalysis.
 7. The method of claim 3, further comprising updating thewaveform template when at least one of the similarity and thecorrelation between the signal waveform and the waveform template meetsone or more criteria.
 8. The method of claim 7, further comprisingdetecting a level of interferent in the biological sample, wherein thewaveform template is updated when the level of interferent meets one ormore criteria.
 9. The method of claim 2, wherein the step of evaluatingthe signal waveform comprises evaluating a monotonicity of the signalwaveform.
 10. The method of claim 9, wherein the step of evaluating amonotonicity of the signal waveform comprises performing a correlationwaveform analysis of the signal waveform with the waveform template. 11.The method of claim 9, wherein the step of evaluating a monotonicity ofthe signal waveform comprises performing a time-series analysis.
 12. Themethod of claim 1, wherein the step of evaluating the sensor systemcomprises detecting an interferent by evaluating at least one of anamplitude, a change in amplitude, a signal waveform, and a change in asignal waveform of the second signal when the sensor is exposed to thebiological sample.
 13. The method of claim 12, wherein the step ofdetecting an interferent is further based at least in part on acalibrated analyte value.
 14. The method of claim 12, further comprisingcontrolling a display of the sensor system based at least in part on alevel of interferent detected on the second signal.
 15. The method ofclaim 12, further comprising processing the first signal and the secondsignal to obtain a subtracted signal, wherein the step of processing isbased at least in part a level of interferent of the sensor system. 16.The method of claim 1, further comprising determining a level ofreliability of the sensor system by comparing at least one of anamplitude, a change in amplitude, a signal waveform, and a change in asignal waveform of the second signal to one or more criteria.
 17. Themethod of claim 16, further comprising controlling a display of thesensor system based at least in part on the level of reliability of thesensor system.
 18. The method of claim 1, wherein the step of evaluatingcomprises determining a success of a biological sample draw-back from ahost's circulatory system to the analyte sensor.
 19. The method of claim18, further comprising displaying an analyte value measured during thebiological sample draw-back in response to a determination of asuccessful biological sample draw-back.
 20. The method of claim 1,wherein the step of evaluating comprises determining a success ofinfusing the infusion solution such that the biological sample is washedfrom the sensor.
 21. The method of claim 20, wherein the step ofdetermining a success of infusing comprises displaying an analyte valuemeasured in the biological sample after infusing the infusion solutionin response to a determination of a successful infusion.